Hiv integrase inhibitors

ABSTRACT

Hydroxy (tetra- or hexa-)hydronaphthyridine dione compounds of Formula I are inhibitors of HIV integrase and inhibitors of HIV replication: (I) wherein a, R ,1?, R ,2?, R ,3?, R ,4? and R ,5? are defined herein. The compounds are useful in the prevention and treatment of infection by HIV and in the prevention, delay in the onset, and treatment of AIDS. The compounds are employed against HIV infection and AIDS as compounds per se or in the form of pharmaceutically acceptable salts. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines.

This application claims the benefit of U.S. Provisional Application Nos.60/551,625 (filed Mar. 9, 2004) and 60/633,134 (filed Dec. 3, 2004), thedisclosures of which are hereby incorporated by reference in theirentireties.

FIELD OF THE INVENTION

The present invention is directed hydroxy tetrahydro-2,6-naphthyridinedione and hydroxy hexahydro-2,6-naphthyridine dione compounds andpharmaceutically acceptable salts thereof, their synthesis, and theiruse as inhibitors of the HIV integrase enzyme. The compounds andpharmaceutically acceptable salts thereof of the present invention areuseful for preventing or treating infection by HIV and for preventing ortreating or delaying the onset of AIDS.

BACKGROUND OF THE INVENTION

A retrovirus designated human immunodeficiency virus (HIV), particularlythe strains known as HIV type-1 (HIV-1) virus and type-2 (HIV-2) virus,is the etiological agent of the complex disease that includesprogressive destruction of the immune system (acquired immune deficiencysyndrome; AIDS) and degeneration of the central and peripheral nervoussystem. This virus was previously known as LAV, HTLV-III, or ARV. Acommon feature of retrovirus replication is the insertion byvirally-encoded integrase of +proviral DNA into the host cell genome, arequired step in HIV replication in human T-lymphoid and monocytoidcells. Integration is believed to be mediated by integrase in threesteps: assembly of a stable nucleoprotein complex with viral DNAsequences; cleavage of two nucleotides from the 3′ termini of the linearproviral DNA; covalent joining of the recessed 3′ OH termini of theproviral DNA at a staggered cut made at the host target site. The fourthstep in the process, repair synthesis of the resultant gap, may beaccomplished by cellular enzymes.

Nucleotide sequencing of HIV shows the presence of a pol gene in oneopen reading frame [Ratner, L. et al., Nature, 313, 277(1985)]. Aminoacid sequence homology provides evidence that the pol sequence encodesreverse transcriptase, integrase and an HIV protease [Toh, H. et al.,EMBO J. 4, 1267 (1985); Power, M. D. et al., Science, 231, 1567 (1986);Pearl, L. H. et al., Nature, 329, 351 (1987)]. All three enzymes havebeen shown to be essential for the replication of HIV.

It is known that some antiviral compounds which act as inhibitors of HIVreplication are effective agents in the treatment of AIDS and similardiseases, including reverse transcriptase inhibitors such asazidothymidine (AZT) and efavirenz and protease inhibitors such asindinavir and nelfinavir. The compounds of this invention are inhibitorsof HIV integrase and inhibitors of HIV replication. The inhibition ofintegrase in vitro and HIV replication in cells is a direct result ofinhibiting the strand transfer reaction catalyzed by the recombinantintegrase in vitro in HIV infected cells. The particular advantage ofthe present invention is highly specific inhibition of HIV integrase andHIV replication.

The following references are of interest as background:

U.S. Pat. No. 6,380,249, U.S. Pat. No. 6,306,891, and U.S. Pat. No.6,262,055 disclose 2,4-dioxobutyric acids and acid esters useful as HIVintegrase inhibitors.

WO 01/00578 discloses 1-(aromatic- orheteroaromatic-substituted)-3-(heteroaromaticsubstituted)-1,3-propanediones useful as HIV integrase inhibitors.

US 2003/0055071 (corresponding to WO 02/30930), WO 02/30426, and WO02/55079 each disclose certain8-hydroxy-1,6-naphthyridine-7-carboxamides as BEIV integrase inhibitors.

WO 02/036734 discloses certain aza- and polyaza-naphthalenyl ketones tobe HIV integrase inhibitors.

WO 03/016275 discloses certain compounds having integrase inhibitoryactivity.

WO 03/35076 discloses certain 5,6-dihydroxypyrimidine-4-carboxamides asHIV integrase inhibitors, and WO 03/35077 discloses certainN-substituted 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamides asHIV integrase inhibitors.

WO 03/1062204 discloses certain hydroxynaphthyridinone carboxamides thatare useful as HIV integrase inhibitors.

WO 04/004657 discloses certain hydroxypyrrole derivatives that are HIVintegrase inhibitors.

WO 2005/016927 discloses certain nitrogenous condensed ring compoundsthat are HIV integrase inhibitors.

SUMMARY OF THE INVENTION

The present invention is directed to hydroxy polyhydro-2,6-naphthyridinedione compounds. These compounds are useful in the inhibition of HIVintegrase, the prevention of infection by HIV, the treatment ofinfection by HIV and in the prevention, treatment, and delay in theonset of AIDS and/or ARC, either as compounds or their pharmaceuticallyacceptable salts or hydrates (when appropriate), or as pharmaceuticalcomposition ingredients, whether or not in combination with otherHIV/AIDS antivirals, anti-infectives, immunomodulators, antibiotics orvaccines. More particularly, the present invention includes compounds ofFormula I, and pharmaceutically acceptable salts thereof:

wherein:bond

in the ring is a single bond or a double bond;R¹ is —C₁₋₆ alkyl, R^(J), or —C₁₋₆ alkyl substituted with R^(J), whereinR^(J) is:

-   -   (A) (i) aryl or (ii) aryl fused to a 5- or 6-membered        heteroaromatic ring containing from 1 to 4 heteroatoms        independently selected from N, O and S or (iii) aryl substituted        on two adjacent ring carbons with alkylenedioxy, wherein the        aryl or fused aryl or alkylenedioxy aryl is:        -   (a) optionally substituted with from 1 to 5 substituents            each of which is independently:            -   —C₁₋₆ alkyl optionally substituted with —OH, —O—C₁₋₆                alkyl, —O—C₁₋₆ haloalkyl, —CN, —NO₂, —N(R^(a))R^(b),                —C(═O)N(R^(a))R^(b), —C(═O)R^(a), —CO₂R^(a),                —S(O)_(n)R^(a), —SO₂N(R^(a))R^(b), —N(R^(a))C(═O)R^(b),                —N(R^(a))CO₂R^(b), —N(R^(a))SO₂R^(b),                —N(R^(a))SO₂N(R^(a))R^(b), —OC(═O)N(R^(a))R^(b), or                —N(R^(a))C(═O)N(R^(a))R^(b),            -   (2) —O—C₁₋₆ alkyl,            -   (3) —C₁₋₆ haloalkyl,            -   (4) —O—C₁₋₆ haloalkyl,            -   (5) —OH,            -   halogen,            -   (7) —CN,            -   (8) —NO₂,            -   (9) —N(R^(a))R^(b),            -   (10) —C(═O)N(R^(a))R^(b),            -   (11) —C(═O)R^(a),            -   (12) —CO₂R^(a),            -   (13) —SR^(a),            -   (14) —S(═O)R^(a),            -   (15) —SO₂R^(a),            -   (16) —SO₂N(R^(a))R^(b),            -   (17) —N(R^(a))SO₂R^(b),            -   (18) —N(R^(a))SO₂N(R^(a))R^(b),            -   (19) —N(R^(a))C(═O)R^(b),            -   (20) —N(R^(a))C(═O)—C(═O)N(R^(a))R^(b),            -   (21) —N(R^(a))CO₂R^(b), or            -   (22) —N(R^(a))C(═O)N(R^(a))R^(b), and        -   (b) optionally substituted with 1 or 2 substituents each of            which is independently:            -   (1) C₃₋₈ cycloalkyl which is optionally substituted with                from 1 to 4 substituents each of which is independently                halogen, CN, C₁₋₆ alkyl, OH, O—C₁₋₆ alkyl, C₁₋₆                haloalkyl, O—C₁₋₆ haloalkyl, C₁₋₆ alkylene-CN, C₁₋₆                alkylene-OH, or C₁₋₆ alkylene-O—C₁₋₆ alkyl,            -   (2) aryl or C₁₋₆ alkyl substituted with aryl, wherein in                either case the aryl is optionally substituted with from                1 to 5 substituents each of which is independently                halogen, CN, NO₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, OH, O—C₁₋₆                alkyl, O—C₁₋₆ haloalkyl, N(R^(a))R^(b),                C(O)N(R^(a))R^(b), C(O)R^(a), C(O)OR^(a), SR^(a),                S(O)R^(a), S(O)₂R^(a), S(O)₂N(R^(a))R^(b),                S(O)₂N(R^(a))C(O)R^(b), C₁₋₆ alkylene-CN, C₁₋₆                alkylene-NO₂, C₁₋₆ alkylene-OH, C₁₋₆ alkylene-O—C₁₋₆                alkyl, C₁₋₆ alkylene-O—C₁₋₆ haloalkyl, C₁₋₆                alkylene-N(R^(a))R^(b), C₁₋₆ alkylene-C(O)N(R^(a))R^(b),                C₁₋₆ alkylene-C(O)R^(a), C₁₋₆ alkylene-C(O)OR^(a), C₁₋₆                alkylene-SR^(a), C₁₋₆ alkylene-S(O)R^(a), C₁₋₆                alkylene-S(O)₂R^(a), C₁₋₆ alkylene-S(O)₂N(R^(a))R^(b),                or C₁₋₆ alkylene-S(O)₂N(R^(A))C(O)R^(b),            -   (3) —HetA,            -   (4) —C(═O)—HetA, or            -   (5) —HetB;                -   wherein each HetA is independently a C₄₋₇                    azacycloalkyl or a C₃₋₆ diazacycloalkyl, either of                    which is optionally substituted with from 1 to 4                    substituents each of which is independently halogen,                    CN, C₁₋₆ alkyl, OH, oxo, O—C₁₋₆ alkyl, C₁₋₆                    haloalkyl, S(O)₂R^(a), C₁₋₆ alkylene-CN, C₁₋₆                    alkylene-OH, or C₁₋₆ alkylene-O—C₁₋₆ alkyl; and                -   wherein each HetB is independently a 5- or                    6-membered heteroaromatic ring containing from 1 to                    4 heteroatoms independently selected from N, O and                    S, wherein the heteroaromatic ring is optionally                    substituted with from 1 to 4 substituents each of                    which is independently halogen, CN, NO₂, C₁₋₆ alkyl,                    C₁₋₆ haloalkyl, OH, O—C₁₋₆ alkyl, O—C₁₋₆ haloalkyl,                    N(R^(a))R^(b), C(O)N(R^(a))R^(b), C(O)R^(a),                    C(O)OR^(a), SR^(a), S(O)R^(a), S(O)₂R^(a),                    S(O)₂N(R^(a))R^(b), S(O)₂N(R^(a))C(O)R^(b), C₁₋₆                    alkylene-CN, C₁₋₆ alkylene-NO₂, C₁₋₆ alkylene-OH,                    C₁₋₆ alkylene-O—C₁₋₆ alkyl, C₁₋₆ alkylene-O—C₁₋₆                    haloalkyl, C₁₋₆ alkylene-N(R^(a))R^(b), C₁₋₆                    alkylene-C(O)N(R^(a))R^(b), C₁₋₆ alkylene-C(O)R^(a),                    C₁₋₆ alkylene-C(O)OR^(a), C₁₋₆ alkylene-SR^(a), C₁₋₆                    alkylene-S(O)R^(a), C₁₋₆ alkylene-S(O)₂R^(a), C₁₋₆                    alkylene-S(O)₂N(R^(a))R^(b), or C₁₋₆                    alkylene-S(O)₂N(R^(a))C(O)R^(b); or    -   (B) a 5- or 6-membered heteroaromatic ring containing from 1 to        4 heteroatoms independently selected from N, O and S, wherein        the heteroaromatic ring is:        -   (a) optionally substituted with from 1 to 4 substituents            each of which is independently:            -   (1) —C₁₋₆ alkyl optionally substituted with —OH, —O—C₁₋₆                alkyl, —O—C₁₋₆ haloalkyl, —CN, —NO₂, —N(R^(a))R^(b),                —C(═O)N(R^(a))R^(b), —C(═O)R^(a), —CO₂R^(a),                —S(O)_(n)R^(a), —SO₂N(R^(a))R^(b), —N(R^(a))C(═O)R^(b),                —N(R^(a))CO₂R^(b), —N(R^(a))SO₂R^(b),                —N(R^(a))SO₂N(R^(a))R^(b), —OC(═O)N(R^(a))R^(b), or                —N(R^(a))C(═O)N(R^(a))R^(b),            -   (2) —O—C₁₋₆ alkyl,            -   (3) —C₁₋₆ haloalkyl,            -   (4) —O—C₁₋₆ haloalkyl,            -   (5) —OH,            -   (6) halogen,            -   (7) —CN,            -   (8) —NO₂,            -   (9) —N(R^(a))R^(b),            -   (10) —C(═O)N(R^(a))R^(b),            -   (11) —C(═O)R^(a),            -   (12) —CO₂R^(a),            -   (13) —SR^(a),            -   (14) —S(═O)R^(a),            -   (15) —SO₂R^(a),            -   (16) —SO₂N(R^(a))R^(b),            -   (17) —N(R^(a))SO₂R^(b),            -   (18) —N(R^(a))SO₂N(R^(a))R^(b),            -   (19) —N(R^(a))C(═O)R^(b),            -   (20) —N(R^(a))C(═O)—C(═O)N(R^(a))R^(b),            -   (21) —N(R^(a))CO₂R^(b), or            -   (22) —N(R^(a))C(═O)N(R^(a))R^(b), and        -   (b) optionally substituted with 1 or 2 substituents each of            which is independently:            -   (1) C₃₋₈ cycloalkyl which is optionally substituted with                from 1 to 4 substituents each of which is independently                halogen, CN, C₁₋₆ alkyl, OH, O—C₁₋₆ alkyl, C₁₋₆                haloalkyl, O—C₁₋₆ haloalkyl, C₁₋₆ alkylene-CN, C₁₋₆                alkylene-OH, or C₁₋₆ alkylene-O—C₁₋₆ alkyl,            -   (2) aryl or C₁₋₆ alkyl substituted with aryl, wherein in                either case the aryl is optionally substituted with from                1 to 5 substituents each of which is independently                halogen, CN, NO₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, OH, O—C₁₋₆                alkyl, O—C₁₋₆ haloalkyl, N(R^(a))R^(b),                C(O)N(R^(a))R^(b), C(O)R^(a), C(O)OR^(a), SR^(a),                S(O)R^(a), S(O)₂R^(a), S(O)₂N(R^(a))R^(b),                S(O)₂N(R^(a))C(O)R^(b), C₁₋₆ alkylene-CN, C₁₋₆                alkylene-NO₂, C₁₋₆ alkylene-OH, C₁₋₆ alkylene-O—C₁₋₆                alkyl, C₁₋₆ alkylene-O—C₁₋₆ haloalkyl, C₁₋₆                alkylene-N(R^(a))R^(b), C₁₋₆ alkylene-C(O)N(R^(a))R^(b),                C₁₋₆ alkylene-C(O)R^(a), C₁₋₆ alkylene-C(O)OR^(a), C₁₋₆                alkylene-SR^(a), C₁₋₆ alkylene-S(O)R^(a), C₁₋₆                alkylene-S(O)₂R^(a), C₁₋₆ alkylene-S(O)₂N(R^(a))R^(b),                or C₁₋₆ alkylene-S(O)₂N(R^(A))C(O)R^(b),            -   (3) —HetA,            -   (4) —C(═O)—HetA, or            -   (5) —HetB;                -   wherein HetA and HetB are each independently as                    defined above;                    R² is —H or —C₁₋₆ alkyl;                    R³ independently has the same definition as R⁴, with                    the proviso that at least one of R³ and R⁴ is —H or                    —C₁₋₆ alkyl;                    or, as an alternative, when bond                    is a double bond, R² and R³ together with the carbon                    atoms to which each is attached form:    -   (i) a benzene ring which is optionally substituted with a total        of from 1 to 4 substituents wherein (a) from zero to 4        substituents are each independently one of substituents (1)        to (22) as defined in part (A)(a) of the definition of R¹        and (b) from zero to 2 substituents are each independently one        of the substituents (1) to (5) as defined in part (A)(b) of the        definition of R¹, or    -   (ii) a 5- or 6-membered heteroaromatic ring containing from 1 to        4 heteroatoms independently selected from N, O and S, wherein        the heteroaromatic ring is optionally substituted with a total        of from 1 to 3 substituents wherein (a) from zero to 3        substituents are each independently one of substituents (1)        to (22) as defined in part (B)(a) of the definition of R¹        and (b) from zero to 2 substituents are each independently one        of the substituents (1) to (5) as defined in part (B)(b) of the        definition of R¹;        R⁴ is:

-   (1) —H,

-   (2) —C₁₋₆ alkyl,

-   (3) —C₁₋₆ haloalkyl,

-   (4) —C₁₋₆ alkyl substituted with —OH, —O—C₁₋₆ alkyl, —O—C₁₋₆    haloalkyl, —CN, —N(R^(a))R^(b), —C(═O)N(R^(a))R^(b), —C(═O)R^(a),    —CO₂R^(a), —C(═O)—N(R^(a))—C₁₋₆ alkylene-OR^(b) with the proviso    that the —N(R^(a))— moiety and the —OR^(b) moiety are not both    attached to the same carbon of the —C₁₋₆ alkylene-moiety,    —S(O)_(n)R^(a), —SO₂N(R^(a))R^(b), —N(R^(a))C(═O)—R^(b),    —N(R^(a))CO₂R^(b), —N(R^(a))SO₂R^(b), —N(R^(a))SO₂N(R^(a))R^(b),    —N(R^(a))C(═O)N(R^(a))R^(b), or —OC(═O)N(R^(a))R^(b),

-   (5) —C(═O)R^(a),

-   (6) —CO₂R^(a),

-   (7) —C(═O)N(R^(a))R^(b),

-   (8) —C(═O)—N(R^(a))—C₁₋₆ alkylene-OR^(b) with the proviso that the    —N(R^(a))— moiety and the OR^(b) moiety are not both attached to the    same carbon of the —C₁₋₆ alkylene-moiety,

-   (9) —N(R^(a))—C(═O)—R^(b),

-   (10) —N(R^(a))—C(═O)—C(═O)N(R^(a))R^(b),

-   (11) —N(R^(a))SO₂R^(b),

-   (12) —N(R^(a))SO₂N(R^(a))R^(b),

-   (13) —N(R^(a))C(═O)N(R^(a))R^(b),

-   (14) —OC(═O)N(R^(a))R^(b),

-   (15) R^(K),

-   (16) —C(═O)—R^(K),

-   (17) —C(═O)N(R^(a))—R^(K),

-   (18) —C(═O)N(R^(a))—C₁₋₆ alkylene-R^(K),

-   (19) —C₁₋₆ alkyl substituted with —R^(K),

-   (20) —C₁₋₆ alkyl substituted with —C(═O)—R^(K),

-   (21) —C₁₋₆ alkyl substituted with —C(═O)N(R^(a))—R^(K),

-   (22) —C₁₋₆ alkyl substituted with —C(═O)N(R^(a))—C₁₋₆    alkylene-R^(K),

-   (23) —C(═O)N(R^(a))R^(c),

-   (24) —CN,

-   (25) halogen,

-   (26) —N(R^(a))R^(b), or

-   (27) —N(R^(a))CO₂R^(b);    -   wherein R^(K) is    -   (i)C₃₋₈ cycloalkyl which is optionally substituted with from 1        to 4 substituents each of which is independently halogen, CN,        C₁₋₆ alkyl, OH, O—C₁₋₆ alkyl, C₁₋₆ haloalkyl, O—C₁₋₆ haloalkyl,        C₁₋₆ alkylene-CN, C₁₋₆ alkylene-OH, or C₁₋₆ alkylene-O—C₁₋₆        alkyl,    -   (ii) aryl, which is optionally substituted with from 1 to 5        substituents each of which is independently —C₁₋₆ alkyl, —C₁₋₆        alkylene-OH, —C₁₋₆ alkylene-O—C₁₋₆ alkyl, —C₁₋₆ alkylene-O—C₁₋₆        haloalkyl, —C₁₋₆ alkylene-N(R^(a))R^(b), —C₁₋₆        alkylene-C(═O)N(R^(a))R^(b), —C₁₋₆ alkylene-C(═O)R^(a), —C₁₋₆        alkylene-CO₂R^(a), —C₁₋₆ alkylene-S(O)_(n)R^(a), —O—C₁₋₆ alkyl,        —C₁₋₆ haloalkyl, —O—C₁₋₆ haloalkyl, —OH, halogen,        —N(R^(a))R^(b), —C(═O)N(R^(a))R^(b), —C(═O)R^(a), —CO₂R^(a),        —S(O)_(n)R^(a), or —SO₂N(R^(a))R^(b),    -   (iii) HetK, which is a 4- to 7-membered saturated heterocyclic        ring containing at least one carbon atom and from 1 to 4        heteroatoms independently selected from N, O and S, wherein the        heterocyclic ring is:        -   (a) optionally substituted with from 1 to 6 substituents            each of which is independently halogen, —C₁₋₆ alkyl, —C₁₋₆            haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, oxo,            —C(═O)N(R^(a))R^(b), —C(═O)C(═O)N(R^(a))R^(b), —C(═O)R^(a),            —CO₂R^(a), —S(O)_(n)R^(a), or —SO₂N(R^(a))R^(b); and        -   (b) optionally substituted with:            -   (1) C₃₋₈ cycloalkyl which is optionally substituted with                from 1 to 4 substituents each of which is independently                halogen, CN, C₁₋₆ alkyl, OH, O—C₁₋₆ alkyl, C₁₋₆                haloalkyl, Q-C₁₋₆ haloalkyl, C₁₋₆ alkylene-CN, C₁₋₆                alkylene-OH, or C₁₋₆ alkylene-O—C₁₋₆ alkyl,            -   (2) aryl which is optionally substituted with from 1 to                5 substituents each of which is independently halogen,                CN, NO₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, OH, O—C₁₋₆ alkyl,                O—C₁₋₆ haloalkyl, N(R^(a))R^(b), C(O)N(R^(a))R^(b),                C(O)R^(a), C(O)OR^(a), SR^(a), S(O)R^(a), S(O)₂R^(a),                S(O)₂N(R^(a))R^(b), S(O)₂N(R^(a))C(O)R^(b), C₁₋₆                alkylene-CN, C₁₋₆ alkylene-NO₂, C₁₋₆ alkylene-OH, C₁₋₆                alkylene-O—C₁₋₆ alkyl, C₁₋₆ alkylene-O—C₁₋₆ haloalkyl,                C₁₋₆ alkylene-N(R^(a))R^(b), C₁₋₆                alkylene-C(O)N(R^(a))R^(b), C₁₋₆ alkylene-C(O)R^(a),                C₁₋₆ alkylene-C(O)OR^(a), C₁₋₆ alkylene-SR^(a), C₁₋₆                alkylene-S(O)R^(a), C₁₋₆ alkylene-S(O)₂R^(a), C₁₋₆                alkylene-S(O)₂N(R^(a))R^(b), or C₁₋₆                alkylene-S(O)₂N(R^(A))C(O)R^(b), or            -   (3) HetC,                -   wherein HetC is a 5- or 6-membered heteroaromatic                    ring containing from 1 to 4 heteroatoms                    independently selected from N, O and S, wherein the                    heteroaromatic ring is optionally fused with a                    benzene ring, and the optionally fused                    heteroaromatic ring is optionally substituted with                    from 1 to 4 substituents each of which is                    independently halogen, CN, NO₂, C₁₋₆ alkyl, C₁₋₆                    haloalkyl, OH, O—C₁₋₆ alkyl, O—C₁₋₆ haloalkyl,                    N(R^(a))R^(b), C(O)N(R^(a))R^(b), C(O)R^(a),                    C(O)OR^(a), SR^(a), S(O)R^(a), S(O)₂R^(a),                    S(O)₂N(R^(a))R^(b), S(O)₂N(R^(a))C(O)R^(b), C₁₋₆                    alkylene-CN, C₁₋₆ alkylene-NO₂, C₁₋₆ alkylene-OH,                    C₁₋₆ alkylene-O—C₁₋₆ alkyl, C₁₋₆ alkylene-O—C₁₋₆                    haloalkyl, C₁₋₆ alkylene-N(R^(a))R^(b), C₁₋₆                    alkylene-C(O)N(R^(a))R^(b), C₁₋₆ alkylene-C(O)R^(a),                    C₁₋₆ alkylene-C(O)OR^(a), C₁₋₆ alkylene-SR^(a), C₁₋₆                    alkylene-S(O)R^(a), C₁₋₆ alkylene-S(O)₂R^(a), C₁₋₆                    alkylene-S(O)₂N(R^(a))R^(b), or C₁₋₆                    alkylene-S(O)₂N(R^(a))C(O)R^(b), or    -   (iv) —HetL, which is a 5- or 6-membered heteroaromatic ring        containing from 1 to 4 heteroatoms independently selected from        N, O and S, wherein the heteroaromatic ring is optionally        substituted with from 1 to 4 substituents each of which is        independently halogen, CN, NO₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, OH,        O—C₁₋₆ alkyl, O—C₁₋₆ haloalkyl, N(R^(a))R^(b),        C(O)N(R^(a))R^(b), C(O)R^(a), C(O)OR^(a), SR^(a), S(O)R^(a),        S(O)₂R^(a), S(O)₂N(R^(a))R^(b), S(O)₂N(R^(a))C(O)R^(b), C₁₋₆        alkylene-CN, C₁₋₆ alkylene-NO₂, C₁₋₆ alkylene-OH, C₁₋₆        alkylene-O—C₁₋₆ alkyl, C₁₋₆ alkylene-O—C₁₋₆ haloalkyl, C₁₋₆        alkylene-N(R^(a))R^(b), C₁₋₆ alkylene-C(O)N(R^(a))R^(b), C₁₋₆        alkylene-C(O)R^(a), C₁₋₆ alkylene-C(O)OR^(a), C₁₋₆        alkylene-SR^(a), C₁₋₆ alkylene-S(O)R^(a), C₁₋₆        alkylene-S(O)₂R^(a), C₁₋₆ alkylene-S(O)₂N(R^(a))R^(b), or C₁₋₆        alkylene-S(O)₂N(R^(a))C(O)R^(b);        R⁵ is:    -   (1) —H,    -   (2) —C₁₋₆ alkyl,    -   (3) —C₃₋₈ cycloalkyl optionally substituted with from 1 to 4        substituents each of which is independently halogen, CN, C₁₋₆        alkyl, OH, O—C₁₋₆ alkyl, C₁₋₆ haloalkyl, O—C₁₋₆ haloalkyl, C₁₋₆        alkylene-CN, C₁₋₆ alkylene-OH, or C₁₋₆ alkylene-O—C₁₋₆ alkyl,    -   (4) —C₁₋₆ alkyl substituted with C₃₋₈ cycloalkyl, wherein the        cycloalkyl is optionally substituted with from 1 to 4        substituents each of which is independently halogen, CN, C₁₋₆        alkyl, OH, O—C₁₋₆ alkyl, C₁₋₆ haloalkyl, O—C₁₋₆ haloalkyl, C₁₋₆        alkylene-CN, C₁₋₆ alkylene-OH, or C₁₋₆ alkylene-O—C₁₋₆ alkyl,    -   (5) —C₁₋₆ alkyl substituted with aryl, wherein the aryl is        optionally substituted with from 1 to 5 substituents each of        which is independently halogen, CN, NO₂, C₁₋₆ alkyl, C₁₋₆        haloalkyl, OH, O—C₁₋₆ alkyl, O—C₁₋₆ haloalkyl, N(R^(a))R^(b),        C(O)N(R^(a))R^(b), C(O)R^(a), C(O)OR^(a), SR^(a), S(O)R^(a),        S(O)₂R^(a), S(O)₂N(R^(a))R^(b), S(O)₂N(R^(a))C(O)R^(b), C₁₋₆        alkylene-CN, C₁₋₆ alkylene-NO₂, C₁₋₆ alkylene-OH, C₁₋₆        alkylene-O—C₁₋₆ alkyl, C₁₋₆ alkylene-O—C₁₋₆ haloalkyl, C₁₋₆        alkylene-N(R^(a))R^(b), C₁₋₆ alkylene-C(O)N(R^(a))R^(b), C₁₋₆        alkylene-C(O)R^(a), C₁₋₆ alkylene-C(O)OR^(a), C₁₋₆        alkylene-SR^(a), C₁₋₆ alkylene-S(O)R^(a), C₁₋₆        alkylene-S(O)₂R^(a), C₁₋₆ alkylene-S(O)₂N(R^(a))R^(b), or C₁₋₆        alkylene-S(O)₂N(R^(A))C(O)R^(b),    -   (6) —C₁₋₆ alkyl substituted with HetD, wherein HetD is:        -   (i) a 4- to 7-membered saturated heterocyclic ring            containing at least one carbon atom and from 1 to 4            heteroatoms independently selected from N, O and S, wherein            the heterocyclic ring is optionally substituted with from 1            to 5 substituents each of which is independently halogen,            —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆            haloalkyl, oxo, —C(═O)N(R^(a))R^(b),            —C(═O)C(═O)N(R^(a))R^(b), —C(═O)R^(a), —CO₂R^(a),            —S(O)_(n)R^(a), or —SO₂N(R^(a))R^(b); or        -   (ii) a 5- or 6-membered heteroaromatic ring containing from            1 to 4 heteroatoms independently selected from N, O and S,            wherein the heteroaromatic ring is optionally substituted            with from 1 to 4 substituents each of which is independently            —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆            haloalkyl, or hydroxy,    -   (7) aryl, which is optionally substituted with from 1 to 5        substituents each of which is independently —C₁₋₆ alkyl, —C₁₋₆        alkylene-OH, —C₁₋₆ alkylene-O—C₁₋₆ alkyl, —C₁₋₆ alkylene-O—C₁₋₆        haloalkyl, —C₁₋₆ alkylene-N(R^(a))R^(b), —C₁₋₆        alkylene-C(═O)N(R^(a))R^(b), —C₁₋₆ alkylene-C(═O)R^(a), —C₁₋₆        alkylene-CO₂R^(a), —C₁₋₆ alkylene-S(O)_(n)R^(a), —O—C₁₋₆ alkyl,        —C₁₋₆ haloalkyl, —O—C₁₋₆ haloalkyl, —OH, halogen, —CN, —NO₂,        —N(R^(a))R^(b), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)—C₁₋₆        haloalkyl, —N(R^(a))C(═O)N(R^(a))R^(b), —N(R^(a))CO₂R^(b),        —N(R^(a))S(O)_(n)R^(b), —C(═O)N(R^(d))R^(e), —C(═O)R^(a),        —CO₂R^(a), —S(O)_(n)R^(a), or —SO₂N(R^(d))R^(e),    -   (8) a 5- or 6-membered heteroaromatic ring containing from 1 to        4 heteroatoms independently selected from N, O and S, wherein        the heteroaromatic ring is optionally substituted with from 1 to        4 substituents each of which is independently halogen, CN, NO₂,        C₁₋₆ alkyl, C₁₋₆ haloalkyl, OH, O—C₁₋₆ alkyl, O—C₁₋₆ haloalkyl,        N(R^(a))R^(b), C(O)N(R^(a))R^(b), C(O)R^(a), C(O)OR^(a), SR^(a),        S(O)R^(a), S(O)₂R^(a), S(O)₂N(R^(a))R^(b),        S(O)₂N(R^(a))C(O)R^(b), C₁₋₆ alkylene-CN, C₁₋₆ alkylene-NO₂,        C₁₋₆ alkylene-OH, C₁₋₆ alkylene-O—C₁₋₆ alkyl, C₁₋₆        alkylene-O—C₁₋₆ haloalkyl, C₁₋₆ alkylene-N(R^(a))R^(b), C₁₋₆        alkylene-C(O)N(R^(a))R^(b), C₁₋₆ alkylene-C(O)R^(a), C₁₋₆        alkylene-C(O)OR^(a), C₁₋₆ alkylene-SR^(a), C₁₋₆        alkylene-S(O)R^(a), C₁₋₆ alkylene-S(O)₂R^(a), C₁₋₆        alkylene-S(O)₂N(R^(a))R^(b), or C₁₋₆        alkylene-S(O)₂N(R^(a))C(O)R^(b),    -   (9) C₁₋₆ alkyl substituted with —O—C₁₋₆ alkyl, —O—C₁₋₆        haloalkyl, —CN, —N(R^(a))R^(b), —C(═O)N(R^(a))R^(b),        —C(═O)R^(a), —CO₂R^(a), —S(O)_(n)R^(a), —SO₂N(R^(a))R^(b),        —N(R^(a))C(═O)—R^(b), —N(R^(a))CO₂R^(b), or —N(R^(a))SO₂R^(b),        or    -   (10) —C₁₋₆ haloalkyl;        each aryl is independently (i) phenyl, (ii) a 9- or 10-membered        bicyclic, fused carbocylic ring system in which at least one        ring is aromatic, or (iii) an 11- to 14-membered tricyclic,        fused carbocyclic ring system in which at least one ring is        aromatic;        each R^(a) is independently H or C₁₋₆ alkyl;        each R^(b) is independently H or C₁₋₆ alkyl;        R^(c) is C₁₋₆ haloalkyl or C₁₋₆ alkyl substituted with        —C(═O)N(R^(a))R^(b), —C(═O)R^(a), —CO₂R^(a), —S(O)_(n)R^(a),        —SO₂N(R^(a))R^(b), N(R^(a))R^(b), —N(R^(a))C(═O)—R^(b),        —N(R^(a))CO₂R^(b), or —N(R^(a))SO₂R^(b);        each R^(d) and R^(e) are independently H or C₁₋₆ alkyl, or        together with the N atom to which they are attached form a 4- to        7-membered saturated or mono-unsaturated heterocyclic ring        optionally containing a heteroatom in addition to the nitrogen        attached to R^(d) and R^(e) selected from N, O, and S, wherein        the S is optionally oxidized to S(O) or S(O)₂, and wherein the        saturated or mono-unsaturated heterocyclic ring is optionally        substituted with from 1 to 4 substituents each of which is        independently halogen, —CN, —C₁₋₆ alkyl, —OH, oxo, —O—C₁₋₆        alkyl, —C₁₋₆ haloalkyl, —C(═O)R^(a), —CO₂R^(a), —S(O)_(n)R^(a),        —SO₂N(R^(a))R^(b), —N(R^(a))C(═O)—R^(b), —N(R^(a))CO₂R^(b), or        —N(R^(a))SO₂R^(b); and        each n is independently an integer equal to zero, 1, or 2.

The present invention also includes pharmaceutical compositionscontaining a compound of the present invention and methods of preparingsuch pharmaceutical compositions. The present invention further includesmethods of treating AIDS, methods of delaying the onset of AIDS, methodsof preventing AIDS, methods of preventing infection by HIV, and methodsof treating infection by HIV.

Other embodiments, aspects and features of the present invention areeither further described in or will be apparent from the ensuingdescription, examples and appended claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention includes compounds of Formula I above, andpharmaceutically acceptable salts thereof. These compounds and theirpharmaceutically acceptable salts are HIV integrase inhibitors (e.g.,HIV-1 integrase inhibitors).

A first embodiment of the present invention is a compound of Formula I,or a pharmaceutically acceptable salt thereof, wherein:

R¹ is —C₁₋₆ alkyl substituted with R^(J), wherein R^(J) is:

-   -   (A) aryl or aryl fused to a 5- or 6-membered heteroaromatic ring        containing from 1 to 4 heteroatoms independently selected from        N, O and S, wherein the aryl or fused aryl is:        -   (a) optionally substituted with from 1 to 5 substituents            each of which is independently:            -   (1) —C₁₋₆ alkyl optionally substituted with —OH, —O—C₁₋₆                alkyl, —O—C₁₋₆ haloalkyl, —CN, —NO₂, —N(R^(a))R^(b),                —C(═O)N(R^(a))R^(b), —C(═O)R^(a), —CO₂R^(a),                —S(O)_(n)R^(a), —SO₂N(R^(a))R^(b), —N(R^(a))C(═O)R^(b),                —N(R^(a))CO₂R^(b), —N(R^(a))SO₂R^(b),                —N(R^(a))SO₂N(R^(a))R^(b), —OC(═O)N(R^(a))R^(b), or                —N(R^(a))C(═O)N(R^(a))R^(b),            -   (2) —O—C₁₋₆ alkyl,            -   (3) —C₁₋₆ haloalkyl,            -   (4) —O—C₁₋₆ haloalkyl,            -   (5) —OH,            -   (6) halogen,            -   (7) —CN,            -   (8) —NO₂,            -   (9) —N(R^(a))R^(b),            -   (10) —C(═O)N(R^(a))R^(b),            -   (11) —C(═O)R^(a),            -   (12) —CO₂R^(a),            -   (13) —SR^(a),            -   (14) —S(═O)R^(a),            -   (15) —SO₂R^(a),            -   (16) —SO₂N(R^(a))R^(b),            -   (17) —N(R^(a))SO₂R^(b),            -   (18) —N(R^(a))SO₂N(R^(a))R^(b),            -   (19) —N(R^(a))C(═O)R^(b),            -   (20) —N(R^(a))C(═O)—C(═O)N(R^(a))R^(b), or            -   (21) —N(R^(a))CO₂R^(b), and        -   (b) optionally substituted with 1 or 2 substituents each of            which is independently:            -   (1) phenyl,            -   (2) benzyl,            -   (3) —HetA,            -   (4) —C(═O)—HetA, or            -   (5) —HetB;                -   wherein each HetA is independently a C₄₋₇                    azacycloalkyl or a C₃₋₆ diazacycloalkyl, either of                    which is optionally substituted with from 1 to 4                    substituents each of which is independently oxo or                    C₁₋₆ alkyl; and                -   wherein each HetB is a 5- or 6-membered                    heteroaromatic ring containing from 1 to 4                    heteroatoms independently selected from N, O and S,                    wherein the heteroaromatic ring is optionally                    substituted with from 1 to 4 substituents each of                    which is independently halogen, —C₁₋₆ alkyl, —C₁₋₆                    haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, or                    hydroxy; or    -   (B) a 5- or 6-membered heteroaromatic ring containing from 1 to        4 heteroatoms independently selected from N, O and S; wherein        the heteroaromatic ring is        -   (i) optionally substituted with from 1 to 4 substituents            each of which is independently halogen, —C₁₋₆ alkyl, —C₁₋₆            haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, or hydroxy; and        -   (ii) optionally substituted with 1 or 2 substituents each of            which is independently aryl or —C₁₋₆ alkyl substituted with            aryl;            R² and R³ are each independently —H or —C₁₋₆ alkyl;            R⁴ is:    -   (1) —H,    -   (2) —C₁₋₆ alkyl,    -   (3) —C₁₋₆ haloalkyl,    -   (4) —C₁₋₆ alkyl substituted with —OH, —O—C₁₋₆ alkyl, —O—C₁₋₆        haloalkyl, —CN, —N(R^(a))R^(b), —C(═O)N(R^(a))R^(b),        —C(═O)R^(a), —CO₂R^(a), —C(═O)—N(R^(a))—C₁₋₆ alkylene-OR^(b)        with the proviso that the —N(R^(a))— moiety and the —OR^(b)        moiety are not both attached to the same carbon of the —C₁₋₆        alkylene-moiety, —S(O)_(n)R^(a), —SO₂N(R^(a))R^(b),        —N(R^(a))C(═O)—R^(b), —N(R^(a))CO₂R^(b), —N(R^(a))SO₂R^(b),        —N(R^(a))SO₂N(R^(a))R^(b), —N(R^(a))C(═O)N(R^(a))R^(b), or        —OC(═O)N(R^(a))R^(b),    -   (5) —C(═O)R^(a),    -   (6) —CO₂R^(a),    -   (7) —C(═O)N(R^(a))R^(b),    -   (8) —C(═O)—N(R^(a))—C₁₋₆ alkylene-OR^(b) with the proviso that        the —N(R^(a))— moiety and the —OR^(b) moiety are not both        attached to the same carbon of the —C₁₋₆ alkylene-moiety,    -   (9) —N(R^(a))—C(═O)—R^(b),    -   (10) —N(R^(a))—C(═O)—C(═O)N(R^(a))R^(b),    -   (11) —N(R^(a))SO₂R^(b),    -   (12) —N(R^(a))SO₂N(R^(a))R^(b),    -   (13) —N(R^(a))SO₂N(R^(a))R^(b),    -   (14) —N(R^(a))C(═O)N(R^(a))R^(b),    -   (15) —OC(═O)N(R^(a))R^(b),    -   (16) —R^(K),    -   (17) —C(═O)—R^(K),    -   (18) —C(═O)N(R^(a))—R^(K),    -   (19) —C(═O)N(R^(a))—C₁₋₆ alkylene-R^(K),    -   (20) —C₁₋₆ alkyl substituted with —R^(K),    -   (21) —C₁₋₆ alkyl substituted with —C(═O)—R^(K),    -   (22) —C₁₋₆ alkyl substituted with —C(═O)N(R^(a))—R^(K), or    -   (23) —C₁₋₆ alkyl substituted with —C(═O)N(R^(a))—C₁₋₆        alkylene-R^(K);        -   wherein R^(K) is        -   (i)C₃₋₈ cycloalkyl, which is optionally substituted with            from 1 to 4 substituents each of which is independently            halogen, —OH, —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl,            or —O—C₁₋₆ haloalkyl,        -   (ii) aryl, which is optionally substituted with from 1 to 5            substituents each of which is independently —C₁₋₆ alkyl,            —C₁₋₆ alkylene-OH, —C₁₋₆ alkylene-O—C₁₋₆ alkyl, —C₁₋₆            alkylene-O—C₁₋₆ haloalkyl, —C₁₋₆ alkylene-N(R^(a))R^(b),            —C₁₋₆ alkylene-C(═O)N(R^(a))R^(b), —C₁₋₆            alkylene-C(═O)R^(a), —C₁₋₆ alkylene-CO₂R^(a), —C₁₋₆            alkylene-S(O)_(n)R^(a), —O—C₁₋₆ alkyl, —C₁₋₆ haloalkyl,            —O—C₁₋₆ haloalkyl, —OH, halogen, —N(R^(a))R^(b),            —C(═O)N(R^(a))R^(b), —C(═O)R^(a), —CO₂R^(a), —S(O)_(n)R^(a),            or —SO₂N(R^(a))R^(b);        -   (iii) HetK, which is a 4- to 7-membered saturated            heterocyclic ring containing at least one carbon atom and            from 1 to 4 heteroatoms independently selected from N, O and            S, wherein the heterocyclic ring is:            -   (a) optionally substituted with from 1 to 6 substituents                each of which is independently halogen, —C₁₋₆ alkyl,                —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, or                oxo; and            -   (b) optionally substituted with aryl or HetC;                -   wherein HetC is a 5- or 6-membered heteroaromatic                    ring containing from 1 to 4 heteroatoms                    independently selected from N, O and S, wherein the                    heteroaromatic ring is optionally fused with a                    benzene ring, and the optionally fused                    heteroaromatic ring is optionally substituted with                    from 1 to 4 substituents each of which is                    independently —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆                    alkyl, —O—C₁₋₆ haloalkyl, or hydroxy; or        -   (iv) —HetL, which is a 5- or 6-membered heteroaromatic ring            containing from 1 to 4 heteroatoms independently selected            from N, O and S, wherein the heteroaromatic ring is            optionally substituted with from 1 to 4 substituents each of            which is independently halogen, —C₁₋₆ alkyl, —C₁₋₆            haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, or hydroxy;            R⁵ is:    -   (1) —H,    -   (2) —C₁₋₆ alkyl,    -   (3) —C₃₋₈ cycloalkyl optionally substituted with from 1 to 4        substituents each of which is independently halogen, —OH, —C₁₋₆        alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, or —O—C₁₋₆ haloalkyl,    -   (4) —C₁₋₆ alkyl substituted with C₃₋₈ cycloalkyl, wherein the        cycloalkyl is optionally substituted with from 1 to 4        substituents each of which is independently halogen, —OH, —C₁₋₆        alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, or —O—C₁₋₆ haloalkyl,    -   (5) —C₁₋₆ alkyl substituted with aryl, wherein the aryl is        optionally substituted with from 1 to 5 substituents each of        which is independently —C₁₋₆ alkyl, —C₁₋₆ alkylene-OH, —C₁₋₆        alkylene-O—C₁₋₆ alkyl, —C₁₋₆ alkylene-O—C₁₋₆ haloalkyl, —C₁₋₆        alkylene-N(R^(a))R^(b), —C₁₋₆ alkylene-C(═O)N(R^(a))R^(b), —C₁₋₆        alkylene-C(═O)R^(a), —C₁₋₆ alkylene-CO₂R^(a), —C₁₋₆        alkylene-S(O)_(n)R^(a), —O—C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆        haloalkyl, —OH, halogen, —N(R^(a))R^(b), —C(═O)N(R^(a))R^(b),        —C(═O)R^(a), —CO₂R^(a), —S(O)_(n)R^(a), or —SO₂N(R^(a))R^(b);    -   (6) —C₁₋₆ alkyl substituted with HetD, wherein HetD is        -   (i) a 4- to 7-membered saturated heterocyclic ring            containing at least one carbon atom and from 1 to 4            heteroatoms independently selected from N, O and S, wherein            the heterocyclic ring is optionally substituted with from 1            to 5 substituents each of which is independently halogen,            —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆            haloalkyl, or oxo; or        -   (ii) a 5- or 6-membered heteroaromatic ring containing from            1 to 4 heteroatoms independently selected from N, O and S,            wherein the heteroaromatic ring is optionally substituted            with from 1 to 4 substituents each of which is independently            —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆            haloalkyl, or hydroxy;            each aryl is independently phenyl, naphthyl, or indenyl;            and all other variables are as originally defined (i.e., as            defined in the Summary of the Invention).

A second embodiment of the present invention is a compound of Formula I,or a pharmaceutically acceptable salt thereof, wherein R¹ is —C₁₋₆ alkylsubstituted with R^(J); and all other variables are as originallydefined (i.e., as defined in the Summary of the Invention) or as definedin the first embodiment. In an aspect of this embodiment, R¹ is—CH₂—R^(J).

A third embodiment of the present invention is a compound of Formula I,or a pharmaceutically acceptable salt thereof, wherein R¹ is R^(J) or—CH₂—R^(J) (e.g., R¹ is —CH₂—R^(J)), wherein R^(J) is phenyl,quinolinyl, isoquinolinyl, cinnolinyl, or quinazolinyl, any of which is:

-   -   (a) optionally substituted with from 1 to 4 substituents each of        which is independently:        -   (1) —C₁₋₄ alkyl,        -   (2) —O—C₁₋₄ alkyl,        -   (3) —C₁₋₄ haloalkyl,        -   (4) —O—C₁₋₄ haloalkyl,        -   (5) halogen,        -   (6) —CN,        -   (7) —N(R^(a))R^(b),        -   (8) —C(═O)N(R^(a))R^(b),        -   (9) —S(═O)R^(a),        -   (10) —SO₂R^(a),        -   (11) —N(R^(a))SO₂R^(b),        -   (12) —N(R^(a))SO₂N(R^(a))R^(b),        -   (13) —N(R^(a))C(═O)R^(b), or        -   (14) —N(R^(a))C(═O)—C(═O)N(R^(a))R^(b), and    -   (b) optionally substituted with 1 or 2 substituents each of        which is independently:        -   (1) —HetA, or        -   (2) —C(═O)—HetA;            -   wherein each HetA is independently a C₄₋₇ azacycloalkyl                or a C₃₋₆ diazacycloalkyl, either of which is optionally                substituted with 1 or 2 substituents each of which is                independently oxo or C₁₋₄ alkyl; and with the proviso                that when HetA is attached to the rest of the compound                via the —C(═O)— moiety, the HetA is attached to the                —C(═O)— via a ring N atom;                and all other variables are as originally defined or as                defined in the first embodiment.

A fourth embodiment of the present invention is a compound of Formula I,or a pharmaceutically acceptable salt thereof, wherein R¹ is R^(J) or—CH₂—R^(J) (e.g., R¹ is —CH₂—R^(J)), wherein R^(J) is phenyl optionallysubstituted with from 1 to 3 substituents each of which isindependently:

(1) —C₁₋₄ alkyl,

(2) —C₁₋₄ haloalkyl,

(3) —O—C₁₋₄ alkyl,

(4) halogen,

(5) —CN,

(6) —C(═O)N(R^(a))R^(b), or

(7) —SO₂R^(a);

and all other variables are as originally defined or as defined in thefirst embodiment.

A fifth embodiment of the present invention is a compound of Formula I,or a pharmaceutically acceptable salt thereof, wherein R¹ is:

the asterisk * denotes the point of attachment of R¹ to the rest of thecompound; X¹ and X² are each independently:

(1) —H,

(2) —C₁₋₆ alkyl,

(3) —OH

(4) —O—C₁₋₆ alkyl,

(5) —C₁₋₆ haloalkyl,

(6) —O—C₁₋₆ haloalkyl,

(7) halogen,

(8) —CN,

(9) —N(R^(a))R^(b),

(10) —C(═O)N(R^(a))R^(b),

(11) —SR^(a),

(12) —S(O)R^(a),

(13) SO₂R^(a),

(14) —N(R^(a))SO₂R^(b),

(15) —N(R^(a))SO₂N(R^(a))R^(b),

(16) —N(R^(a))C(═O)R^(b),

(17) —N(R^(a))C(═O)—C(═O)N(R^(a))R^(b),

(18) —HetA,

(19) —C(═O)—HetA, or

(20) HetB;

-   -   wherein each HetA is independently a C₄₋₅ azacycloalkyl or a        C₃₋₄ diazacycloalkyl, either of which is optionally substituted        with 1 or 2 substituents each of which is independently oxo or        C₁₋₆ alkyl; and with the proviso that when HetA is attached to        the rest of the compound via the —C(═O)— moiety, the HetA is        attached to the —C(═O)— via a ring N atom; and    -   each HetB is independently a 5- or 6-membered heteroaromatic        ring containing from 1 to 4 heteroatoms independently selected        from N, O and S, wherein the heteroaromatic ring is optionally        substituted with from 1 to 4 substituents each of which is        independently halogen, —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆        alkyl, —O—C₁₋₆ haloalkyl, or hydroxy;        or alternatively X¹ and X² are respectively located on adjacent        carbons in the phenyl ring and together form methylenedioxy or        ethylenedioxy;        X³ is:

(1) —H,

(2) —C₁₋₆ alkyl,

(3) —O—C₁₋₆ alkyl,

(4) —C₁₋₆ haloalkyl,

(5) —O—C₁₋₆ haloalkyl, or

(6) halogen;

and all other variables are as originally defined or as defined in thefirst embodiment.

An aspect of the fifth embodiment is a compound of Formula I, or apharmaceutically acceptable salt thereof, wherein X¹ and X² in thedefinition of R¹ are each independently: (1) —H, (2) —C₁₋₄ alkyl, (3)—C₁₋₄ haloalkyl, (4) —OH, (5) —O—C₁₋₄ alkyl, (6) halogen, (7) —CN, (8)—C(═O)NH₂, (9) —C(═O)NH(—C₁₋₄ alkyl), (10) —C(═O)N(—C₁₋₄ alkyl)₂, or(11) —SO₂—C₁₋₄ alkyl; or alternatively X¹ and X² are respectivelylocated on adjacent carbons in the phenyl ring and together formmethylenedioxy or ethylenedioxy; X³ is —H, halogen, —C₁₋₄ alkyl, or—O—C₁₋₄ alkyl; and all other variables are as defined in the fifthembodiment.

A sixth embodiment of the present invention is a compound of Formula I,or a pharmaceutically acceptable salt thereof, wherein R¹ is:

the asterisk * denotes the point of attachment of R¹ to the rest of thecompound; X¹ and X² are each independently as defined in the fifthembodiment, except that neither X¹ nor X² is —OH; and all othervariables are as originally defined or as defined in the firstembodiment.

An aspect of the sixth embodiment is a compound of Formula I, or apharmaceutically acceptable salt thereof, wherein X¹ and X² in thedefinition of R¹ are each independently: (1) —H, (2) —C₁₋₄ alkyl, (3)—C₁₋₄ haloalkyl, (4) —O—C₁₋₄ alkyl, (5) halogen, (6) —CN, (7) —C(═O)NH₂,(8) —C(═O)NH(—C₁₋₄ alkyl), (9) —C(═O)N(—C₁₋₄ alkyl)₂, or (10) —SO₂—C₁₋₄alkyl; and all other variables are as defined in the sixth embodiment.

Another aspect of the sixth embodiment is a compound of Formula I, or apharmaceutically acceptable salt thereof, wherein X¹ in the definitionof R¹ is (1) —H, (2) bromo, (3) chloro, (4) fluoro, or (5) methoxy; andX² in the definition of R¹ is (1) —H, (2) bromo, (3) chloro, (4) fluoro,(5) methyl, (6) methoxy, (7) —CF₃, or (8) —OCF₃.

A seventh embodiment of the present invention is a compound of FormulaI, or a pharmaceutically acceptable salt thereof, wherein R¹ is:

the asterisk * denotes the point of attachment of R¹ to the rest of thecompound; X¹ is: (1) —H, (2) bromo, (3) chloro, (4) fluoro, or (5)methoxy; X² is: (1) —H, (2) bromo, (3) chloro, (4) fluoro, (5) methoxy,(6) —C₁₋₄ alkyl, (7) —CF₃, (8) —OCF₃, (9) —CN, or (10) —SO₂(C₁₋₄ alkyl);and all other variables are as originally defined, or as defined in thefirst embodiment.

An aspect of the seventh embodiment is a compound of Formula I, or apharmaceutically acceptable salt thereof, wherein X¹ in the definitionof R¹ is (1) —H, (2) bromo, (3) chloro, (4) fluoro, or (5) methoxy; andX² in the definition of R¹ is (1) —H, (2) bromo, (3) chloro, (4) fluoro,(5) methyl, (6) methoxy, (7) —CF₃, or (8) —OCF₃.

An eighth embodiment of the present invention is a compound of FormulaI, or a pharmaceutically acceptable salt thereof, wherein R¹ isCH₂—R^(J); R^(J) is 4-fluorophenyl or 3-chloro-4-fluorophenyl; and allother variables are as originally defined or as defined in the firstembodiment.

A ninth embodiment of the present invention is a compound of Formula I,or a pharmaceutically acceptable salt thereof, wherein R¹ is CH₂—R^(J);R^(J) is 4-fluorophenyl; and all other variables are as originallydefined or as defined in the first embodiment.

A tenth embodiment of the present invention is a compound of Formula I,or a pharmaceutically acceptable salt thereof, wherein R¹ is CH₂—R^(J);R^(J) is 3-chloro-4-fluorophenyl; and all other variables are asoriginally defined or as defined in the first embodiment.

An eleventh embodiment of the present invention is a compound of FormulaI, or a pharmaceutically acceptable salt thereof, wherein R⁴ is:

-   -   (1) —H,    -   (2) —C₁₋₆ alkyl,    -   (3) —C₁₋₆ haloalkyl,    -   (4) —C₁₋₆ alkyl substituted with —OH, —O—C₁₋₆ alkyl, —O—C₁₋₆        haloalkyl, —CN, —N(R^(a))R^(b), —C(═O)N(R^(a))R^(b),        —C(═O)R^(a), —CO₂R^(a), —C(═O)—N(R^(a))—(CH₂)₂₋₃—OR^(b),        —S(O)_(n)R^(a), —SO₂N(R^(a))R^(b), —N(R^(a))C(═O)—R^(b),        —N(R^(a))CO₂R^(b), —N(R^(a))SO₂R^(b), —N(R^(a))SO₂N(R^(a))R^(b),        —N(R^(a))C(═O)N(R^(a))R^(b), or —OC(═O)N(R^(a))R^(b),    -   (5) —C(═O)R^(a),    -   (6) —CO₂R^(a),    -   (7) —C(═O)N(R^(a))R^(b),    -   (8) —C(═O)—N(R^(a))—(CH₂)₂₋₃—OR^(b),    -   (9) —N(R^(a))—C(═O)—R^(b),    -   (10) —N(R^(a))—C(═O)—C(═O)N(R^(a))R^(b),    -   (11) —N(R^(a))SO₂R^(b),    -   (12) —N(R^(a))SO₂N(R^(a))R^(b),    -   (13) —R^(K),    -   (14) —C(═O)—R^(K),    -   (15) —C(═O)N(R^(a))—R^(K),    -   (16) —C(═O)N(R^(a))—C₁₋₆ alkylene-R^(K),    -   (17) —(CH₂)₁₋₃—R^(K),    -   (18) —(CH₂)₁₋₃—C(═O)—R^(K),    -   (19) —(CH₂)₁₋₃—C(═O)N(R^(a))—R^(K), or    -   (20) —(CH₂)₁₋₃—C(═O)N(R^(a))—C₁₋₆ alkylene-R^(K);        and all other variables are as originally defined or as defined        in any one of the preceding embodiments.

A twelfth embodiment of the present invention is a compound of FormulaI, or a pharmaceutically acceptable salt thereof, wherein R⁴ is: (1) —H,(2) —C₁₋₆ alkyl, (3) —C₁₋₆ fluoroalkyl, (4) —CO₂R^(a), (5)—C(═O)N(R^(a))R^(b), (6) —C(═O)—N(R^(a))—(CH₂)₂₋₃—OR^(b), (7)—N(R^(a))—C(═O)R^(b), (8) —N(R^(a))SO₂R^(b), (9)—N(R^(a))SO₂N(R^(a))R^(b), (10) —R^(K), (11) —C(═O)—R^(K), (12)—C(═O)N(R^(a))—(CH₂)₀₋₂—R^(K) (13) —C(═O)N(R^(a))R^(c), or (14) halogen;and all other variables are as originally defined or as defined in anyone of the preceding embodiments.

A thirteenth embodiment of the present invention is a compound ofFormula I, or a pharmaceutically acceptable salt thereof, wherein R⁴ is:(1) —H, (2) —C₁₋₆ alkyl, (3) —C₁₋₆ fluoroalkyl, (4) —CO₂R^(a), (5)—C(═O)N(R^(a))R^(b), (6) —C(═O)—N(R^(a))—(CH₂)₂₋₃—OR^(b), (7)—N(R^(a))—C(═O)—R^(b), (8) —N(R^(a))SO₂R^(b), (9)—N(R^(a))SO₂N(R^(a))R^(b), (10) —R^(K), (11) —C(═O)—R^(K), or (12)—C(═O)N(R^(a))—(CH₂)₀₋₂—R^(K); and all other variables are as originallydefined or as defined in any one of the preceding embodiments.

An aspect of the eleventh, twelfth, and thirteenth embodiment is acompound of Formula I, or a pharmaceutically acceptable thereof, whereinR^(K) is:

-   -   (i)C₃₋₆ cycloalkyl, which is optionally substituted with from 1        to 4 substituents each of which is independently halogen, —OH,        —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, or —O—C₁₋₆        haloalkyl,    -   (ii) phenyl, which is optionally substituted with from 1 to 5        substituents each of which is independently —C₁₋₆ alkyl, —C₁₋₆        alkylene-OH, —C₁₋₆ alkylene-O—C₁₋₆ alkyl, —C₁₋₆ alkylene-O—C₁₋₆        haloalkyl, —C₁₋₆ alkylene-N(R^(a))R^(b), —C₁₋₆        alkylene-C(═O)N(R^(a))R^(b), —C₁₋₆ alkylene-C(═O)R^(a), —C₁₋₆        alkylene-CO₂R^(a), —C₁₋₆ alkylene-S(O)_(n)R^(a), —O—C₁₋₆ alkyl,        —C₁₋₆ haloalkyl, —O—C₁₋₆ haloalkyl, —OH, halogen,        —N(R^(a))R^(b), —C(═O)N(R^(a))R^(b), —C(═O)R^(a), —CO₂R^(a),        —S(O)_(n)R^(a), or —SO₂N(R^(a))R^(b);    -   (iii) HetK, which is a 5- or 6-membered saturated heterocyclic        ring containing at least one carbon atom and a total of from 1        to 4 heteroatoms independently selected from 1 to 4 N atoms,        from 0 to 2 O atoms, and from 0 to 2 S atoms, wherein the        heterocyclic ring is optionally substituted with from 1 to 4        substituents each of which is independently halogen, —C₁₋₆        alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, or        oxo; or    -   (iv) —HetL, which is a 5- or 6-membered heteroaromatic ring        containing a total of from 1 to 4 heteroatoms independently        selected from 1 to 4 N atoms, from 0 to 2 O atoms, and from 0 to        2 S atoms, wherein the heteroaromatic ring is optionally        substituted with from 1 to 3 substituents each of which is        independently halogen, —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆        alkyl, or —O—C₁₋₆ haloalkyl;        and all other variables are as defined in the eleventh, twelfth,        or thirteenth embodiment.

A fourteenth embodiment of the present invention is a compound ofFormula I, or a pharmaceutically acceptable salt thereof, wherein R⁴ is:(1) —H, (2) —C₁₋₄ alkyl, (3) —CO₂H, (4) —C(═O)—O—C₁₋₄ alkyl, (5)—C(═O)NH₂, (6) —C(═O)NH—C₁₋₄ alkyl, (7) —C(═O)N(C₁₋₄ alkyl)₂, (8)—C(═O)—NH—(CH₂)₂₋₃—O—C₁₋₄ alkyl, (9) —C(═O)—N(C₁₋₄alkyl)-(CH₂)₂₋₃—O—C₁₋₄ alkyl, (10) —HetK, (11) —C(═O)—HetK, (12)—C(═O)NH—(CH₂)₀₋₁—(C₃₋₆ cycloalkyl), (13) —C(═O)N(C₁₋₄alkyl)-(CH₂)₀₋₁—(C₃₋₆ cycloalkyl) (14) —C(═O)NH—CH₂-phenyl, or (15)—C(═O)N(C₁₋₄ alkyl)-CH₂-phenyl; wherein:

-   -   HetK is a 5- or 6-membered saturated heterocyclic ring        containing at least one carbon atom and a total of from 1 to 4        heteroatoms independently selected from 1 to 4 N atoms, from 0        to 2 O atoms, and from 0 to 2 S atoms, wherein the heterocyclic        ring is optionally substituted with from 1 to 3 substituents        each of which is independently —C₁₋₄ alkyl or oxo; and with the        proviso that when HetK is attached to the rest of the compound        via the —C(═O)— moiety, the HetK is attached to the —C(═O)— via        a ring N atom;    -   the cycloalkyl in (12) or (13) is optionally substituted with        from 1 to 4 substituents each of which is independently halogen,        —C₁₋₄ alkyl, —CF₃, —O—C₁₋₄ alkyl, or —OCF₃; and    -   the phenyl in (14) or (15) is optionally substituted with from 1        to 4 substituents each of which is independently halogen, —C₁₋₄        alkyl, —O—C₁₋₄ alkyl, —CF₃, or —OCF₃;        and all other variables are as originally defined or as defined        in any one of the preceding embodiments.

A fifteenth embodiment of the present invention is a compound of FormulaI, or a pharmaceutically acceptable salt thereof, wherein R⁴ is: (1)—CO₂R^(a), (2) —C(═O)N(R^(a))R^(b), (3) —C(═O)—N(R^(a))—(CH₂)₂₋₃—OR^(b),(4) —N(R^(a))C(═O)R^(b), (5) —N(R^(a))SO₂R^(b), (6) —HetK, (7)—C(═O)—HetK, (8) —C(═O)N(R^(a))—(CH₂)₀₋₁—(C₃₋₆ cycloalkyl), wherein thecycloalkyl is optionally substituted with from 1 to 4 substituents eachof which is independently halogen, —C₁₋₆ alkyl, —CF₃, —O—C₁₋₆ alkyl, or—OCF₃, or (9) —C(═O)N(R^(a))—CH₂-phenyl, wherein the phenyl isoptionally substituted with from 1 to 4 substituents each of which isindependently —C₁₋₆ alkyl, —O—C₁₋₆ alkyl, —CF₃, —OCF₃, or halogen; andall other variables are as originally defined or as defined in any oneof the preceding embodiments.

An aspect of the fifteenth embodiment is a compound of Formula I, or apharmaceutically acceptable salt thereof, wherein HetK is a 5- or6-membered saturated heterocyclic ring containing at least one carbonatom and a total of from 1 to 4 heteroatoms independently selected from1 to 4 N atoms, from 0 to 2 O atoms, and from 0 to 2 S atoms, whereinthe heterocyclic ring is optionally substituted with from 1 to 4substituents each of which is independently —C₁₋₆ alkyl or oxo; and withthe proviso that when HetK is attached to the rest of the compound viathe —C(═O)— moiety, the HetK is attached to the —C(═O)— via a ring Natom; and all other variables are as defined in the fifteenth 5embodiment.

Another aspect of the fifteenth embodiment is a compound of Formula I,or a pharmaceutically acceptable salt thereof, wherein:

(a) when HetK is directly attached to the rest of the compound, HetK is:

(b) when HetK is attached to the rest of the compound via the —C(═O)—moiety, HetK is:

wherein the asterisk * denotes the point of attachment to the rest ofthe compound; and all other variables are as defined in the fifteenthembodiment.

A sixteenth embodiment of the present invention is a compound of FormulaI, or a pharmaceutically acceptable salt thereof, wherein R⁴ is: (1)—CO₂H, (2) —C(═O)—O—C₁₋₄ alkyl, (3) —C(═O)NH₂, (4) —C(═O)NH—C₁₋₄ alkyl,(5) —C(═O)N(C₁₋₄ alkyl)₂, (6) —C(═O)—NH—(CH₂)₂₋₃—O—C₁₋₄ alkyl, (7)—C(═O)—N(C₁₋₄ alkyl)-(CH₂)₂₋₃—O—C₁₋₄ alkyl, (8) —NHC(═O)—C₁₋₄ alkyl, (9)—N(C₁₋₄ alkyl)C(═O)—C₁₋₄ alkyl, (10) —NHSO₂—C₁₋₄ alkyl, (11) —N(C₁₋₄alkyl)SO₂—C₁₋₄ alkyl, (12) —C(═O)—HetK, wherein HetK is:

and wherein the asterisk * denotes the point of attachment to the restof the compound, (13) —C(═O)NH—(CH₂)₀₋₁—(C₃₋₆ cycloalkyl), (14)—C(═O)N(C₁₋₄ alkyl)-(CH₂)₀₋₁—(C₃₋₆ cycloalkyl), (15) —C(═)NH—CH₂-phenyl,or (16) —C(═O)N(C₁₋₄ alkyl)-CH₂-phenyl; and all other variables are asoriginally defined or as defined in any one of the precedingembodiments.

A seventeenth embodiment of the present invention is identical to thesixteenth embodiment, except that HetK is:

In an aspect of this embodiment, HetK is:

An eighteenth embodiment of the present invention is a compound ofFormula I, or a pharmaceutically acceptable salt thereof, wherein R⁴ is:(1) —C(═O)—O—C₁₋₃ alkyl, (2) —C(═O)NH—C₁₋₃ alkyl, (3) —C(═O)N(C₁₋₃alkyl)₂, (4) —C(═O)—N(C₁₋₃ alkyl)-(CH₂)₂—O—C₁₋₃ alkyl, (5) —N(C₁₋₃alkyl)C(═O)—C₁₋₃ alkyl, (6) —N(C₁₋₃ alkyl)SO₂—C₁₋₃ alkyl, (7)—C(═O)—HetK, wherein HetK is:

and wherein the asterisk * denotes the point of attachment to the restof the compound, (8) —C(═O)NH—(CH₂)0-1-(cyclopropyl), (9)—C(═O)NH—(CH2)0-1-(cyclobutyl), (10) —C(═O)N(C1-3alkyl)-(CH₂)₀₋₁-cyclopropyl, (11) —C(═O)N(C₁₋₃alkyl)-(CH₂)₀₋₁-cyclobutyl, (12) —C(═O)NH—CH₂-phenyl, or (13)—C(═O)N(C₁₋₃ alkyl)-CH₂ alkyl)-CH₂-phenyl; and all other variables areas originally defined or as defined in any one of the precedingembodiments.

A nineteenth embodiment of the present invention is identical to theeighteenth embodiment, except that HetK is:

In an aspect of this embodiment, Hetk is:

A twentieth embodiment of the present invention is a compound of FormulaI, or a pharmaceutically acceptable salt thereof, wherein R⁵ is:

-   -   (1) —H,    -   (2) —C₁₋₄ alkyl,    -   (3) —C₃₋₆ cycloalkyl optionally substituted with from 1 to 3        substituents each of which is independently halogen, —C₁₋₄        alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl, or —O—C₁₋₄ haloalkyl,    -   (4) —(CH₂)₁₋₂—C₃₋₆ cycloalkyl, wherein the cycloalkyl is        optionally substituted with from 1 to 3 substituents each of        which is independently halogen, —C₁₋₄ alkyl, —C₁₋₄ haloalkyl,        —O—C₁₋₄ alkyl, or —O—C₁₋₄ haloalkyl,    -   (5) —(CH₂)₁₋₂-phenyl or —CH(CH₃)-phenyl, wherein in either case        the phenyl is optionally substituted with from 1 to 4        substituents each of which is independently halogen, —C₁₋₄        alkyl, —C₁₋₄ alkylene-O—C₁₋₄ alkyl, —C₁₋₄ haloalkyl, or —O—C₁₋₄        haloalkyl,    -   (6) —(CH₂)₁₋₂—HetD or —CH(CH₃)—HetD, wherein in either case HetD        is:        -   (i) a 4- to 7-membered saturated heterocyclic ring            containing a total of from 1 to 3 heteroatoms independently            selected from 1 to 2 N atoms, from zero to 1 O atom and from            zero to 1 S atom, wherein heterocyclic ring is attached to            the rest of the molecule via a ring N atom, and the            heterocyclic ring is optionally substituted with from 1 to 4            substituents each of which is independently —C₁₋₄ alkyl,            —C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, oxo,            —C(═O)N(R^(a))R^(b), —C(═O)R^(a), —CO₂R^(a), —SO₂R^(a), or            —SO₂N(R^(a))R^(b), or        -   (ii) a 5- or 6-membered heteroaromatic ring containing from            1 to 4 heteroatoms independently selected from N, O and S,            wherein the heteroaromatic ring is optionally substituted            with from 1 to 4 substituents each of which is independently            —C₁₋₄ alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄            haloalkyl, or hydroxyl,    -   (7) phenyl which is optionally substituted with from 1 to 4        substituents each of which is independently —C₁₋₄ alkyl, —C₁₋₄        haloalkyl, —O—C₁₋₄ haloalkyl, —OH, halogen, —CN, —NO₂,        —N(R^(a))R^(b), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)—C₁₋₄        haloalkyl, —N(R^(a))C(═O)N(R^(a))R^(b), —N(R^(a))CO₂R^(b),        —N(R^(a))S(O)_(n)R^(b), —C(═O)N(R^(d))R^(e), —C(═O)R^(a),        —CO₂R^(a), —SO₂R^(a), or —SO₂N(R^(d))R^(e),    -   (8) a 5- or 6-membered heteroaromatic ring containing from 1 to        4 heteroatoms independently selected from N, O and S, wherein        the heteroaromatic ring is optionally substituted with from 1 to        4 substituents each of which is independently —C₁₋₄ alkyl, —C₁₋₄        haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, or hydroxyl,    -   (9) C₁₋₄ alkyl substituted with —O—C₁₋₄ alkyl, —CN,        —N(R^(a))R^(b), —C(═O)N(R^(a))R^(b), —C(═O)R^(a), —CO₂R^(a),        —SO₂R^(a), —SO₂N(R^(a))R^(b), —N(R^(a))C(═O)—R^(b),        —N(R^(a))CO₂R^(b), or —N(R^(a))SO₂R^(b), or    -   (10) —C₁₋₄ haloalkyl;        and all other variables are as originally defined or as defined        in any one of the preceding embodiments.

A twenty-first embodiment of the present invention is a compound ofFormula I, or a pharmaceutically acceptable salt thereof, wherein R⁵ is:

-   -   (1) —H,    -   (2) —C₁₋₄ alkyl,    -   (3) —C₃₋₆ cycloalkyl optionally substituted with from 1 to 3        substituents each of which is independently halogen, —C₁₋₄        alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl, or —O—C₁₋₄ haloalkyl,    -   (4) —(CH₂)₁₋₂—C₃₋₆ cycloalkyl, wherein the cycloalkyl is        optionally substituted with from 1 to 3 substituents each of        which is independently halogen, —C₁₋₄ alkyl, —C₁₋₄ haloalkyl,        —O—C₁₋₄ alkyl, or —O—C₁₋₄ haloalkyl,    -   (5) —(CH₂)₁₋₂-phenyl, wherein the phenyl is optionally        substituted with from 1 to 4 substituents each of which is        independently halogen, —C₁₋₄ alkyl, —C₁₋₄ alkylene-O—C₁₋₄ alkyl,        —C₁₋₄ haloalkyl, or —O—C₁₋₄ haloalkyl, or    -   (6) —(CH₂)₁₋₂—HetD;        and all other variables are as originally defined or as defined        in any one of the preceding embodiments.

An aspect of the twenty-first embodiment is a compound of Formula I, ora pharmaceutically acceptable salt thereof, wherein: HetD is a 5- or6-membered heteroaromatic ring containing from 1 to 4 heteroatomsindependently selected from N, O and S, wherein the heteroaromatic ringis optionally substituted with from 1 to 4 substituents each of which isindependently —C₁₋₄ alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄haloalkyl, or hydroxy; and all other variables are as defined in thetwenty-first embodiment. In a feature of this aspect, all othervariables are as defined in the fifteenth embodiment (or an aspectthereof).

A twenty-second embodiment of the present invention is a compound ofFormula I, or a pharmaceutically acceptable salt thereof, wherein R⁵ is:(1) —H, (2) —C₁₋₄ alkyl, (3) —C₃₋₆ cycloalkyl, (4) —CH₂—C₃₋₆ cycloalkyl,or (5) —CH₂-phenyl; and all other variables are as originally defined oras defined in any one of the preceding embodiments.

A twenty-third embodiment of the present invention is a compound ofFormula I, or a pharmaceutically acceptable salt thereof, wherein R⁵ is:(1) —H, (2) —C₁₋₄ alkyl, (3) cyclopropyl, (4) cyclobutyl, (5)—CH₂-cyclopropyl, (6) —CH₂-cyclobutyl, or (5) —CH₂-phenyl; and all othervariables are as originally defined or as defined in any one of thepreceding embodiments.

A twenty-fourth embodiment of the present invention is a compound ofFormula I, or a pharmaceutically acceptable salt thereof, wherein R⁵ is—H or —C₁₋₄ alkyl; and all other variables are as originally defined oras defined in any one of the preceding embodiments. In an aspect of thisembodiment, R⁵ is —C₁₋₄ alkyl. In other aspect of this embodiment, R⁵ ismethyl, isopropyl, or isobutyl.

A twenty-fifth embodiment of the present invention is a compound ofFormula I, or a pharmaceutically acceptable salt thereof, wherein R⁵ is—H; and all other variables are as originally defined or as defined inany one of the preceding embodiments.

A twenty-sixth embodiment of the present invention is a compound ofFormula I, or a pharmaceutically acceptable salt thereof, wherein R² andR³ are each independently —H or —C₁₋₆ alkyl; and all other variables areas originally defined or as defined in any one of the precedingembodiments. In an aspect of this embodiment, R² and R³ are eachindependently —H or —C₁₋₄ alkyl. In another aspect of this embodiment,R² and R³ are both —H.

A twenty-seventh embodiment of the present invention is a compound ofFormula I, wherein each R^(a) and R^(b) is independently H or C₁₋₃alkyl; and all other variables are as originally defined or as definedin any one of the preceding embodiments.

A twenty-eighth embodiment of the present invention is a compound ofFormula I, wherein each R^(a) and R^(b) is independently H or methyl;and all other variables are as originally defined or as defined in anyone of the preceding embodiments.

A twenty-ninth embodiment of the present invention is a compound ofFormula I, wherein bond

in the ring is a single bond; and all other variables are as originallydefined or as defined in any one of the preceding embodiments.

A first class of the present invention includes compounds of Formula II,and pharmaceutically acceptable salts thereof:

wherein:bond

in the ring is a single bond or a double bond (e.g., is a single bond);X¹ and X² are each independently:

-   -   (1) —H,    -   (2) —C₁₋₆ alkyl,    -   (3) —OH (4) —O—C₁₋₆ alkyl,    -   (5) —C₁₋₆ haloalkyl,    -   (6) —O—C₁₋₆ haloalkyl,    -   (7) halogen,    -   (8) —CN,    -   (9) —N(R^(a))R^(b),    -   (10) —C(═O)N(R^(a))R^(b),    -   (11) —SR^(a),    -   (12) —S(O)R^(a),    -   (13) SO₂R^(a),    -   (14) —N(R^(a))SO₂R^(b),    -   (15) —N(R^(a))SO₂N(R^(a))R^(b),    -   (16) —N(R^(a))C(═O)R^(b),    -   (17) —N(R^(a))C(═O)—C(═O)N(R^(a))R^(b),    -   (18) —HetA,    -   (19) —C(═O)—HetA, or    -   (20) HetB;        -   wherein each HetA is independently a C₄₋₅ azacycloalkyl or a            C₃₋₄ diazacycloalkyl, either of which is optionally            substituted with 1 or 2 substituents each of which is            independently oxo or C₁₋₆ alkyl; and with the proviso that            when HetA is attached to the rest of the compound via the            —C(═O)— moiety, the HetA is attached to the —C(═O)— via a            ring N atom; and        -   each HetB is independently a 5- or 6-membered heteroaromatic            ring containing from 1 to 4 heteroatoms independently            selected from N, O and S, wherein the heteroaromatic ring is            optionally substituted with from 1 to 4 substituents each of            which is independently halogen, —C₁₋₆ alkyl, —C₁₋₆            haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, or hydroxy;            or alternatively X¹ and X² are respectively located on            adjacent carbons in the phenyl ring and together form            methylenedioxy or ethylenedioxy;            X³ is:    -   (1) —H,    -   (2) —C₁₋₆ alkyl,    -   (3) —O—C₁₋₆ alkyl,    -   (4) —C₁₋₆ haloalkyl,    -   (5) —O—C₁₋₆ haloalkyl, or    -   (6) halogen;        R⁴ is:    -   (1) —C₁₋₆ alkyl,    -   (2) —CO₂R^(a),    -   (3) —C(═O)N(R^(a))R^(b),    -   (4) —C(═O)—N(R^(a))—(CH₂)₂₋₃—OR^(b),    -   (5) —N(R^(a))C(═O)R^(b),    -   (6) —N(R^(a))SO₂R^(b),    -   (7) —C₃₋₆ cycloalkyl, which is optionally substituted with from        1 to 4 substituents each of which is independently halogen,        —C₁₋₆ alkyl, —CF₃, —O—C₁₋₆ alkyl, or —OCF₃,    -   (8) —HetK,    -   (9) —C(═O)—HetK,    -   (10) —C(═O)N(R^(a))—HetK,    -   (11) —C(═O)N(R^(a))—(CH₂)₀₋₂—(C₃₋₆ cycloalkyl), wherein the        cycloalkyl is optionally substituted with from 1 to 4        substituents each of which is independently halogen, —C₁₋₆        alkyl, —CF₃, —O—C₁₋₆ alkyl, or —OCF₃, or    -   (12) —C(═O)N(R^(a))—CH₂-phenyl, wherein the phenyl is optionally        substituted with from 1 to 4 substituents each of which is        independently —C₁₋₆ alkyl, —O—C₁₋₆ alkyl, —CF₃, —OCF₃, or        halogen;    -   (13) -HetL,    -   (14) —C(═O)N(R^(a))R^(c), or    -   (15) halogen;        -   wherein HetK is a 5- or 6-membered saturated heterocyclic            ring containing a total of from 1 to 4 heteroatoms            independently selected from 1 to 4 N atoms, from 0 to 2 O            atoms, and from 0 to 2 S atoms, wherein the heterocyclic            ring is optionally substituted with (i) from 1 to 4            substituents each of which is independently —C₁₋₆ alkyl,            oxo, halogen, —C(═O)N(R^(a))R^(b), —C(═O)C(═O)N(R^(a))R^(b),            —C(═O)R^(a), —CO₂R^(a), —SO₂R^(a), or —SO₂N(R^(a))R^(b)            and (ii) from zero to 1 C₃₋₆ cycloalkyl; and with the            proviso that when HetK is attached to the rest of the            compound via the —C(═O)— moiety, the HetK is attached to the            —C(═O)— via a ring N atom;        -   wherein HetL is a 5- or 6-membered heteroaromatic ring            containing from 1 to 4 heteroatoms independently selected            from N, O and S, wherein the heteroaromatic ring is            optionally substituted with from 1 to 4 substituents each of            which is independently —C₁₋₆ alkyl or —OH;            R⁵ is:    -   (1) —H,    -   (2) —C₁₋₆ alkyl,    -   (3) —C₃₋₆ cycloalkyl,    -   (4) —(CH₂)₁₋₂—C₃₋₆ cycloalkyl,    -   (5) —CH₂-phenyl wherein the phenyl is optionally substituted        with from 1 to 4 substituents each of which is independently        halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, or —O—C₁₋₆        haloalkyl,    -   (6) —(CH₂)₁₋₂—HetD, wherein HetD is a 4- to 7-membered saturated        heterocyclic ring containing from 1 to 2 heteroatoms        independently selected from 1 to 2 N atoms, from zero to 1 O        atom and from zero to 1 S atom, wherein the heterocyclic ring is        attached to the rest of the molecule via a ring N atom, and the        heterocyclic ring is optionally substituted with from 1 to 4        substituents each of which is independently —C₁₋₆ alkyl, —C₁₋₆        haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, oxo,        —C(═O)N(R^(a))R^(b), —C(═O)R^(a), —CO₂R^(a), —SO₂R^(a), or        —SO₂N(R^(a))R^(b),    -   (7) phenyl which is optionally substituted with from 1 to 4        substituents each of which is independently —C₁₋₆ alkyl, —O—C₁₋₆        alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ haloalkyl, —OH, halogen, —CN,        —NO₂, —C(═O)R^(a), —CO₂R^(a), —SO₂R^(a), —N(R^(a))C(═O)—C₁₋₆        haloalkyl, —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)N(R^(a))R^(b),        —N(R^(a))CO₂R^(b), —N(R^(a))SO₂R^(b), —C(═O)N(R^(d))R^(e), or        —SO₂N(R^(d))R^(e);    -   (8) a 5- or 6-membered heteroaromatic ring containing from 1 to        4 heteroatoms independently selected from N, O and S, wherein        the heteroaromatic ring is optionally substituted with from 1 to        4 substituents each of which is independently —C₁₋₆ alkyl, —C₁₋₆        haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, or —OH,    -   (9) C₁₋₆ alkyl substituted with —O—C₁₋₆ alkyl, —CN,        —N(R^(a))R^(b), —C(═O)N(R^(a))R^(b), —C(═O)R^(a), —CO₂R^(a),        —SO₂R^(a), or —SO₂N(R^(a))R^(b), or    -   (10) —C₁₋₆ haloalkyl;        each R^(a) is independently H or C₁₋₆ alkyl;        each R^(b) is independently H or C₁₋₆ alkyl;        R^(c) is C₁₋₆ haloalkyl or C₁₋₆ alkyl substituted with        —CO₂R^(a), —SO₂R^(a), —SO₂N(R^(a))R^(b), or N(R^(a))R^(b); and        each R^(d) and R^(e) are independently H or C₁₋₆ alkyl, or        together with the N atom to which they are attached form a 4- to        7-membered saturated heterocyclic ring optionally containing a        heteroatom in addition to the nitrogen attached to R^(d) and        R^(e) selected from N, O, and S, wherein the S is optionally        oxidized to S(O) or S(O)₂, and wherein the saturated        heterocyclic ring is optionally substituted with from 1 to 4        substituents each of which is independently halogen, —CN, —C₁₋₆        alkyl, —OH, oxo, —O—C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —C(═O)R^(a),        —CO₂R^(a), —SO₂R^(a), or —SO₂N(R^(a))R^(b).

A first sub-class of the first class includes compounds of Formula IIa,and pharmaceutically acceptable salts thereof, wherein

wherein:X¹ and X² are each independently: (1) —H, (2) —C₁₋₆ alkyl, (3) —O—C₁₋₆alkyl, (4) —C₁₋₆ haloalkyl, (5) —O—C₁₋₆ haloalkyl, (6) halogen, (7) —CN,(8) —N(R^(a))R^(b), (9) —C(═O)N(R^(a))R^(b), (10) —S(O)_(n)R^(a),wherein n is an integer equal to zero, 1, or 2, (11) —N(R^(a))SO₂R^(b),(12) —N(R^(a))SO₂N(R^(a))R^(b), (13) —N(R^(a))C(═O)R^(b), (14)—N(R^(a))C(═O)—C(═O)N(R^(a))R^(b), (15) —HetA, (16) —C(═O)—HetA, or (17)HetB;R⁴ is: (1) —CO₂R^(a), (2) —C(═O)N(R^(a))R^(b), (3)—C(═O)—N(R^(a))—(CH₂)₂₋₃—OR^(b), (4) —N(R^(a))C(═O)R^(b), (5)—N(R^(a))SO₂R^(b), (6) —HetK, (7) —C(═O)—HetK, (8)—C(═O)N(R^(a))—(CH₂)₀₋₁—(C₃₋₆ cycloalkyl), wherein the cycloalkyl isoptionally substituted with from 1 to 4 substituents each of which isindependently halogen, —C₁₋₆ alkyl, —CF₃, —O—C₁₋₆ alkyl, or —OCF₃, or(9) —C(═O)N(R^(a))—CH₂-phenyl, wherein the phenyl is optionallysubstituted with from 1 to 4 substituents each of which is independently—C₁₋₆ alkyl, —O—C₁₋₆ alkyl, —CF₃, —OCF₃, or halogen;R⁵ is: (1) —H, (2) —C₁₋₆ alkyl, (3) —C₃₋₆ cycloalkyl, (4) —CH₂—C₃₋₆cycloalkyl, or (5) —CH₂-phenyl;and all other variables are as originally defined in the first class.

A second sub-class of the first class includes compounds of Formula II,and pharmaceutically acceptable salts thereof, wherein:

bond

in the ring is a single bond or a double bond (e.g., is a single bond);

X¹ and X² are each independently:

-   -   (1) —H,    -   (2) —C₁₋₄ alkyl,    -   (3) —C₁₋₄ haloalkyl,    -   (4) —OH,    -   (5) —O—C₁₋₄ alkyl,    -   (6) halogen,    -   (7) —CN,    -   (8) —C(═O)NH₂,    -   (9) —C(═O)NH(—C₁₋₄ alkyl),    -   (10) —C(═O)N(—C₁₋₄ alkyl)₂, or    -   (11) —SO₂—C₁₋₄ alkyl;        or alternatively X¹ and X² are respectively located on adjacent        carbons in the phenyl ring and together form methylenedioxy or        ethylenedioxy;        X³ is —H, halogen, —C₁₋₄ alkyl, or —O—C₁₋₄ alkyl;        R⁴ is:    -   (1) —C₁₋₄ alkyl,    -   (2) —CO₂H,    -   (3) —C(═O)—O—C₁₋₄ alkyl,    -   (4) —C(═O)NH₂,    -   (5) —C(═O)NH—C₁₋₅ alkyl,    -   (6) —C(═O)N(C₁₋₄ alkyl)₂,    -   (7) —C(═O)—NH—(CH₂)₂₋₃—O—C₁₋₄ alkyl,    -   (8) —C(═O)—N(C₁₋₄ alkyl)-(CH₂)₂₋₃—O—C₁₋₄ alkyl,    -   (9) —NHC(═O)—C₁₋₄ alkyl,    -   (10) —N(C₁₋₄ alkyl)C(═O)—C₁₋₄ alkyl,    -   (11) —NHSO₂—C₁₋₄ alkyl,    -   (12) —N(C₁₋₄ alkyl)SO₂—C₁₋₄ alkyl,    -   (13) —C₃₋₆ cycloalkyl,    -   (14) —HetK wherein HetK is:        -   wherein the asterisk * denotes the point of attachment to            the rest of the compound,    -   (15) —C(═O)—HetK, wherein HetK is:        wherein the asterisk * denotes the point of attachment to the        rest of the compound,    -   (16) —C(═O)NH-HetK or —C(═O)N(C₁₋₄ alkyl)-HetK, wherein HetK is        a saturated heterocyclic selected from the group consisting of        pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and        thiomorpholinyl, wherein the saturated heterocyclic is        optionally substituted with from 1 to 2 substituents each of        which is independently —C₁₋₄ alkyl, SO₂—C₁₋₄ alkyl, or        —SO₂N(C₁₋₄ alkyl)₂,    -   (17) —C(═O)NH—(CH₂)₀₋₁—(C₃₋₆ cycloalkyl),    -   (18) —C(═O)N(C₁₋₄ alkyl)-(CH₂)₀₋₁—(C₃₋₆ cycloalkyl),    -   (19) —C(═O)NH—CH₂-phenyl, wherein the phenyl is optionally        substituted with 1 or 2 substituents each of which is        independently halogen, —C₁₋₄ alkyl, —CF₃, —O—C₁₋₄ alkyl, or        —OCF₃,    -   (20) —C(═O)N(C₁₋₄ alkyl)-CH₂-phenyl, wherein the phenyl is        optionally substituted with 1 or 2 substituents each of which is        independently halogen, —C₁₋₄ alkyl, —CF₃, —O—C₁₋₄ alkyl, or        —OCF₃,    -   (21) —HetL, wherein HetL is a heteroaromatic ring which is        pyrrolyl, thienyl, furanyl, imidazolyl, oxazolyl, thiazolyl,        isoxazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl,        oxadiazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, wherein the        heteroaromatic ring is optionally substituted with from 1 to 4        substituents each of which is independently halogen or —C₁₋₄        alkyl,    -   (22) —C(O)N(H)—C₁₋₄ haloalkyl,    -   (23) —C(O)N(C₁₋₄ alkyl)-C₁₋₄ haloalkyl,    -   (24) —C(O)N(H)—(CH₂)₁₋₂SO₂—C₁₋₄ alkyl,    -   (25) —C(O)N(C₁₋₄ alkyl)-(CH₂)₁₋₂SO₂—C₁₋₄ alkyl,    -   (26) —C(O)N(H)—(CH₂)₁₋₂N(C₁₋₄ alkyl)₂,    -   (27) —C(O)N(C₁₋₄ alkyl)-(CH₂)₁₋₂N(C₁₋₄ alkyl)₂, or    -   (28) —Cl or —Br; and        R⁵ is:    -   (1) —H,    -   (2) —C₁₋₄ alkyl,    -   (3) —C₃₋₆ cycloalkyl,    -   (4) —CH₂—C₃₋₆ cycloalkyl,    -   (5) —CH₂-phenyl, wherein the phenyl is optionally substituted        with from 1 to 3 substituents each of which is independently        halogen, —C₁₋₄ alkyl, —CF₃, —O—C₁₋₄ alkyl, or —OCF₃,    -   (6) —(CH₂)₁₋₂—HetD, wherein HetD is:        wherein the asterisk * denotes the point of attachment to the        rest of the compound,    -   (7) phenyl which is optionally substituted with —C₁₋₄ alkyl,        —O—C₁₋₄ alkyl, —CF₃, —OCF₃, halogen, —CN, —NO₂, —C(═O)—C₁₋₄        alkyl, —C(═O)—O—C₁₋₄ alkyl, —C(O)NH₂, —C(O)N(H)—C₁₋₄ alkyl,        —C(O)N(C₁₋₄ alkyl)₂, —SO₂—C₁₋₄ alkyl, —SO₂NH₂, —SO₂N(H)—C₁₋₄        alkyl, —SO₂N(C₁₋₄ alkyl)₂, —N(H)C(═O)—C₁₋₄ alkyl, —N(C₁₋₄        alkyl)C(═O)—C₁₋₄ alkyl, —N(H)C(═O)—CF₃, —N(C₁₋₄ alkyl)C(═O)—CF₃,        —N(H)C(═O)N(H)C₁₋₄ alkyl, —N(C₁₋₄ alkyl)C(═O)N(H)C₁₋₄ alkyl,        —N(H)C(═O)N(C₁₋₄ alkyl)₂, —N(C₁₋₄ alkyl)C(═O)N(C₁₋₄ alkyl)₂,        —N(H)C(═O)—O—C₁₋₄ alkyl, —N(C₁₋₄ alkyl)C(═O)—O—C₁₋₄ alkyl,        —N(H)SO₂—C₁₋₄ alkyl, —N(C₁₋₄ alkyl)SO₂—C₁₋₄ alkyl,        -   wherein ring A is pyrrolidinyl, piperidinyl, morpholinyl,            thiomorpholinyl, or piperazinyl optionally substituted on            the other ring nitrogen with methyl or SO₂—CH₃,    -   (8) a 5- or 6-membered heteroaromatic ring which is pyrrolyl,        thienyl, furanyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl,        isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl,        pyrimidinyl, or pyrazinyl, wherein the heteroaromatic ring is        optionally substituted with from 1 to 2 substituents each of        which is independently halogen or —C₁₋₄ alkyl,    -   (9) C₁₋₄ alkyl substituted with —O—C₁₋₄ alkyl, —CN, —NH₂,        —N(H)—C₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, —C(O)NH₂, —C(O)N(H)—C₁₋₄        alkyl, —C(O)N(C₁₋₄ alkyl)₂, —C(═O)—C₁₋₄ alkyl, —C(═O)—O—C₁₋₄        alkyl, —SO₂—C₁₋₄ alkyl, —SO₂NH₂, —SO₂N(H)—C₁₋₄ alkyl, or        —SO₂N(C₁₋₄ alkyl)₂, or    -   (10) —C₁₋₄ fluoroalkyl.

A third sub-class of the first class includes compounds of Formula IIa,and pharmaceutically acceptable salts thereof, wherein:

bond

in the ring is a single bond or a double bond (e.g., is a single bond);

X¹ and X² are each independently: (1) —H, (2) —C₁₋₄ alkyl, (3) —C₁₋₄haloalkyl, (4) —O—C₁₋₄ alkyl, (5) halogen, (6) —CN, (7) —C(═O)NH₂, (8)—C(═O)NH(—C₁₋₄ alkyl), (9) —C(═O)N(—C₁₋₄ alkyl)₂, or (10) —SO₂—C₁₋₄alkyl;

R⁴ is: (1) —CO₂H, (2) —C(═O)—O—C₁₋₄ alkyl, (3) —C(═O)NH₂, (4)—C(═O)NH—C₁₋₄ alkyl, (5) —C(═O)N(C₁₋₄ alkyl)₂, (6)—C(═O)—NH—(CH₂)₂₋₃—O—C₁₋₄ alkyl, (7) —C(═O)—N(C₁₋₄alkyl)-(CH₂)₂₋₃—O—C₁₋₄ alkyl, (8) —NHC(═O)—C₁₋₄ alkyl, (9) —N(C₁₋₄alkyl)C(═O)—C₁₋₄ alkyl, (10) —NHSO₂—C₁₋₄ alkyl, (11) —N(C₁₋₄alkyl)SO₂—C₁₋₄ alkyl, (12) —HetK wherein HetK is:

wherein the asterisk * denotes the point of attachment to the rest ofthe compound,

wherein the asterisk * denotes the point of attachment to the rest ofthe compound, (13) —C(═O)NH—(CH₂)₀₋₁—(C₃₋₆ cycloalkyl), (14)—C(═O)N(C₁₋₄ alkyl)-(CH₂)₀₋₁—(C₃₋₆ cycloalkyl), (15)—C(═O)NH—CH₂-phenyl, or (16) —C(═O)N(C₁₋₄ alkyl)-CH₂-phenyl; and

R⁵ is: (1) —H, (2) —C₁₋₄ alkyl, (3) —C₃₋₆ cycloalkyl, (4) —CH₂—C₃₋₆cycloalkyl, or (5) —CH₂-phenyl.

A fourth sub-class of the first class is identical to the thirdsub-class, except that R⁴ is: (1) —CO₂H, (2) —C(═O)—O—C₁₋₄ alkyl, (3)—C(═O)NH₂, (4) —C(═O)NH—C₁₋₄ alkyl, (5) —C(═O)N(C₁₋₄ alkyl)₂, (6)—C(═O)—NH—(CH₂)₂₋₃—O—C₁₋₄ alkyl, (7) —C(═O)—N(C₁₋₄alkyl)-(CH₂)₂₋₃—O—C₁₋₄ alkyl, (8) —NHC(═O)—C₁₋₄ alkyl, (9) —N(C₁₋₄alkyl)C(═O)—C₁₋₄ alkyl, (10) —NHSO₂—C₁₋₄ alkyl, (1) —N(C₁₋₄alkyl)SO₂—C₁₋₄ alkyl, (12) —C(═O)—HetK, wherein HetK is:

wherein the asterisk * denotes the point of attachment to the rest ofthe compound, (13) —C(═O)NH—(CH₂)₀₋₁—(C₃₋₆ cycloalkyl), (14)—C(═O)N(C₁₋₄ alkyl)-(CH₂)₀₋₁—(C₃₋₆ cycloalkyl), (15)—C(═O)NH—CH₂-phenyl, or (16) —C(═O)N(C₁₋₄ alkyl)-CH₂-phenyl.

A fifth sub-class of the first class is identical to the fourthsub-class, except that HetK is:

A sixth sub-class of the first class is identical to the fourthsub-class, except that HetK is:

A second class of the present invention includes compounds of FormulaIII, and pharmaceutically acceptable salts thereof:

wherein:

X¹ is: (1) —H, (2) bromo, (3) chloro, (4) fluoro, or (5) methoxy;

X² is: (1) —H, (2) bromo, (3) chloro, (4) fluoro, (5) methoxy, (6) —C₁₋₄alkyl, (7) —CF₃, (8) —OCF₃, (9) —CN, or (10) —SO₂(C₁₋₄ alkyl);

R⁴ is: (1) —CO₂H, (2) —C(═O)—O—C₁₋₄ alkyl, (3) —C(═O)NH₂, (4)—C(═O)NH—C₁₋₄ alkyl, (5) —C(═O)N(C₁₋₄ alkyl)₂, (6)—C(═O)—NH—(CH₂)₂₋₃—O—C₁₋₄ alkyl, (7) —C(═O)—N(C₁₋₄alkyl)-(CH₂)₂₋₃—O—C₁₋₄ alkyl, (8) —NHC(═O)—C₁₋₄ alkyl, (9) —N(C₁₋₄alkyl)C(═O)—C₁₋₄ alkyl, (10) —NHSO₂—C₁₋₄ alkyl, (11) —N(C₁₋₄alkyl)SO₂—C₁₋₄ alkyl, (12) —C(═O)—HetK, wherein HetK is:

wherein the asterisk * denotes the point of attachment to the rest ofthe compound,(13) —C(═O)NH—(CH₂)₀₋₁—(C₃₋₆ cycloalkyl), (14) —C(═O)N(C₁₋₄alkyl)-(CH₂)₀₋₁—(C₃₋₆ cycloalkyl), (15) —C(═O)NH—CH₂-phenyl, or (16)—C(═O)N(C₁₋₄ alkyl)-CH₂-phenyl; and

R⁵ is: (1) —H, (2) —C₁₋₄ alkyl, (3) cyclopropyl, (4) cyclobutyl, (5)—CH₂-cyclopropyl, (6) —CH₂-cyclobutyl, or (7) —CH₂-phenyl.

A first sub-class of the second class is identical to the second class,except that HetK is:

A second sub-class of the second class is identical to the second class,except that HetK is:

A third sub-class of the second class is identical to the second class,except that HetK is:

A fourth sub-class of the second class includes compounds of FormulaIII, and pharmaceutically acceptable salts thereof, wherein:

X¹ is fluoro;

X² is —H or chloro;

R⁴ is: (1) —C(═O)—O—C₁₋₃ alkyl, (2) —C(═O)NH—C₁₋₃ alkyl, (3)—C(═O)N(C₁₋₃ alkyl)₂, (4) —C(═O)—N(C₁₋₃ alkyl)-(CH₂)₂—O—C₁₋₃ alkyl, (5)—N(C₁₋₃ alkyl)C(═O)—C₁₋₃ alkyl, (6) —N(C₁₋₁₃ alkyl)SO₂—C₁₋₃ alkyl, (7)—C(═O)—HetK, wherein HetK is:

wherein the asterisk * denotes the point of attachment to the rest ofthe compound, (8) —C(═O)NH—(CH₂)₀₋₁-(cyclopropyl), (9)—C(═O)NH—(CH₂)₀₋₁-(cyclobutyl), (10) —C(═O)N(C₁₋₃alkyl)-(CH₂)₀₋₁-cyclopropyl, (11) —C(═O)N(C₁₋₃alkyl)-(CH₂)₀₋₁-cyclobutyl, (12) —C(═O)NH—CH₂-phenyl, or (13)—C(═O)N(C₁₋₃ alkyl)-CH₂-phenyl; and

R⁵ is —H or C₁₋₄ alkyl.

A fifth sub-class of the second class is identical to the fourthsub-class, except that X² is —H; R⁵ is —H; and HetK is:

A sixth sub-class of the second class is identical to the fifthsub-class, except that HetK is:

A third class of the present invention includes compounds of FormulaIII, and pharmaceutically acceptable salts thereof, wherein X¹ isfluoro; X² is —H or chloro; R⁴ is:

(1) —C(═O)N(C₁₋₃ alkyl)₂,

(2) —C(═O)—HetK, wherein HetK is:

wherein the asterisk * denotes the point of attachment to the rest ofthe compound,

(3) —C(═O)N(C₁₋₃ alkyl)-(CH₂)₀₋₁-cyclopropyl, or

(4) —C(═O)N(C₁₋₃ alkyl)-(CH₂)₀₋₁-cyclobutyl; and

R⁵ is —C₁₋₄ alkyl.

A first sub-class of the third class is identical to the third class,except that R⁴ is —C(═O)N(C₁₋₃ alkyl)₂.

A second sub-class of the third class is identical to the third class,except that R⁴ is —C(═O)N(CH₃)₂.

Another embodiment of the present invention is a compound, or apharmaceutically acceptable salt thereof, selected from the groupconsisting of the compounds set forth in Examples 1 to 87 below. Anaspect of this embodiment is a compound, or a pharmaceuticallyacceptable salt thereof, which is the compound set forth in Example 11,13, or 14. Another aspect of this embodiment is a compound, or apharmaceutically acceptable salt thereof, which is the compound setforth in Example 11 or Example 13. Another aspect of this embodiment isa compound, or a pharmaceutically acceptable salt thereof, which is thecompound set forth in Example 11 (i.e.,6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide).Another aspect of this embodiment is a compound, or a pharmaceuticallyacceptable salt thereof, which is the compound set forth in Example 13(i.e.,6-(3-chloro-4-fluorobenzyl)-4-hydroxy-2-isopropyl-N,N-dimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide).

Other embodiments of the present invention include the following:

(a) A pharmaceutical composition comprising an effective amount of acompound of Formula I and a pharmaceutically acceptable carrier.

(b) A pharmaceutical composition which comprises the product prepared bycombining (e.g., mixing) an effective amount of a compound of Formula Iand a pharmaceutically acceptable carrier.

(c) The pharmaceutical composition of (a) or (b), further comprising aneffective amount of an HIV infection/AIDS treatment agent selected fromthe group consisting of HIV/AIDS antiviral agents, immunomodulators, andanti-infective agents.

(d) The pharmaceutical composition of (c), wherein the HIVinfection/AIDS treatment agent is an antiviral selected from the groupconsisting of HIV protease inhibitors, non-nucleoside HIV reversetranscriptase inhibitors, and nucleoside HIV reverse transcriptaseinhibitors.

(e) A pharmaceutical combination which is (i) a compound of Formula Iand (ii) an HIV infection/AIDS treatment agent selected from the groupconsisting of HIV/AIDS antiviral agents, immunomodulators, andanti-infective agents; wherein the compound of Formula I and the HIVinfection/AIDS treatment agent are each employed in an amount thatrenders the combination effective for inhibiting HIV integrase, fortreating or preventing infection by HIV, or for preventing, treating ordelaying the onset of AIDS.

(f) The combination of (e), wherein the HIV infection/AIDS treatmentagent is an antiviral selected from the group consisting of HIV proteaseinhibitors, non-nucleoside HIV reverse transcriptase inhibitors andnucleoside HIV reverse transcriptase inhibitors.

(g) A method of inhibiting HIV integrase in a subject in need thereofwhich comprises administering to the subject an effective amount of acompound of Formula I.

(h) A method of preventing or treating infection by HIV in a subject inneed thereof which comprises administering to the subject an effectiveamount of a compound of Formula I.

(i) The method of (h), wherein the compound of Formula I is administeredin combination with an effective amount of at least one antiviralselected from the group consisting of HIV protease inhibitors,non-nucleoside HIV reverse transcriptase inhibitors, and nucleoside HIVreverse transcriptase inhibitors.

j) A method of preventing, treating or delaying the onset of AIDS in asubject in need thereof which comprises administering to the subject aneffective amount of a compound of Formula I.

(k) The method of (j), wherein the compound is administered incombination with an effective amount of at least one antiviral selectedfrom the group consisting of HIV protease inhibitors, non-nucleoside HIVreverse transcriptase inhibitors, and nucleoside HIV reversetranscriptase inhibitors P (l) A method of inhibiting HIV integrase in asubject in need thereof which comprises administering to the subject thepharmaceutical composition of (a), (b), (c) or (d) or the combination of(e) or (f).

(m) A method of preventing or treating infection by HIV in a subject inneed thereof which comprises administering to the subject thepharmaceutical composition of (a), (b), (c) or (d) or the combination of(e) or (f).

(n) A method of preventing, treating or delaying the onset of AIDS in asubject in need thereof which comprises administering to the subject thepharmaceutical composition of (a), (b), (c) or (d) or the combination of(e) or (f).

The present invention also includes a compound of the present invention(i) for use in, (ii) for use as a medicament for, or (iii) for use inthe preparation of a medicament for: (a) inhibiting HIV integrase, (b)preventing or treating infection by HIV, or (c) preventing, treating ordelaying the onset of AIDS. In these uses, the compounds of the presentinvention can optionally be employed in combination with one or moreHIV/AIDS treatment agents selected from HIV/AIDS antiviral agents,anti-infective agents, and immunomodulators.

Additional embodiments of the invention include the pharmaceuticalcompositions, combinations and methods set forth in (a)-(n) above andthe uses set forth in the preceding paragraph, wherein the compound ofthe present invention employed therein is a compound of one of theembodiments, aspects, classes, sub-classes, or features of the compoundsdescribed above. In all of these embodiments, the compound mayoptionally be used in the form of a pharmaceutically acceptable salt.

As used herein, the term “alkyl” refers to any linear or branched chainalkyl group having a number of carbon atoms in the specified range.Thus, for example, “C₁₋₆ alkyl” (or “C₁-C₆ alkyl”) refers to all of thehexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- andt-butyl, n- and isopropyl, ethyl and methyl. As another example, “C₁₋₄alkyl” refers to n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl andmethyl.

The term “alkylene” refers to any linear or branched chain alkylenegroup (or alternatively “alkanediyl”) having a number of carbon atoms inthe specified range. Thus, for example, “—C₁₋₆ alkylene-” refers to anyof the C₁ to C₆ linear or branched alkylenes. A class of alkylenes ofparticular interest with respect to the invention is —(CH₂)₁₋₆—, andsub-classes of particular interest include —(CH₂)₁₋₄—, —(CH₂)₁₋₃—,—(CH₂)₁₋₂—, and —CH₂—. Also of interest is the alkylene —CH(CH₃)—.

The term “alkylenedioxy” refers to —O—R—O wherein R is (CH₂)₁₋₃ in whichone of the hydrogens on each methylene is optionally replaced with C₁₋₄alkyl. R is preferably (CH₂)₁₋₂ or CH(CH₃), and is more preferably(CH₂)₁₋₂.

The terms “C(O)” and “C(═O)” are alternative representations ofcarbonyl. The terms “S(O)₂” and “SO₂” are alternative representations ofsulfonyl.

The terms “cycloalkyl” refers to any cyclic ring of an alkane having anumber of carbon atoms in the specified range. Thus, for example, “C₃₋₈cycloalkyl” (or “C₃-C₈ cycloalkyl”) refers to cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

The term “halogen” (or “halo”) refers to fluorine, chlorine, bromine andiodine (alternatively referred to as fluoro, chloro, bromo, and iodo).

The term “haloalkyl” refers to an alkyl group as defined above in whichone or more of the hydrogen atoms has been replaced with a halogen(i.e., F, Cl, Br and/or I). Thus, for example, “C₁₋₆ haloalkyl” (or“C₁-C₆ haloalkyl”) refers to a C₁ to C₆ linear or branched alkyl groupas defined above with one or more halogen substituents. The term“fluoroalkyl” has an analogous meaning except that the halogensubstituents are restricted to fluoro. Suitable fluoroalkyls include theseries (CH₂)₀₋₄CF₃ (i.e., trifluoromethyl, 2,2,2-trifluoroethyl,3,3,3-trifluoro-n-propyl, etc.).

The term “C₄₋₇ azacycloalkyl” (or “C₄-C₇ azacycloalkyl”) means asaturated cyclic ring consisting of one nitrogen and from four to sevencarbon atoms (i.e., pyrrolidinyl, piperidinyl, azepanyl, oroctahydroazocinyl).

The term “C₃₋₆ diazacycloalkyl” (or “C₃-C₆ diazacycloalkyl”) means asaturated cyclic ring consisting of two nitrogens and from three to sixcarbon atoms (e.g., imidazolidinyl, pyrazolidinyl, or piperazinyl).

Unless expressly stated to the contrary, all ranges cited herein areinclusive. For example, a heterocyclic ring described as containing from“1 to 4 heteroatoms” means the ring can contain 1, 2, 3 or 4heteroatoms. It is also to be understood that any range cited hereinincludes within its scope all of the sub-ranges within that range. Thus,for example, a heterocyclic ring described as containing from “1 to 4heteroatoms” is intended to include as aspects thereof, heterocyclicrings containing 2 to 4 heteroatoms, 3 or 4 heteroatoms, 1 to 3heteroatoms, 2 or 3 heteroatoms, 1 or 2 heteroatoms, 1 heteroatom, 2heteroatoms, and so forth.

When any variable (e.g., R^(a), R^(b), or HetA) occurs more than onetime in any constituent or in Formula I or in any other formuladepicting and describing compounds of the invention, its definition oneach occurrence is independent of its definition at every otheroccurrence. Also, combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

The term “substituted” (e.g., as in “is optionally substituted with from1 to 5 substituents . . . ”) includes mono- and poly-substitution by anamed substituent to the extent such single and multiple substitution(including multiple substitution at the same site) is chemicallyallowed. Unless expressly stated to the contrary, substitution by anamed substituent is permitted on any atom in a ring (e.g., aryl, aheteroaromatic ring, or a saturated heterocyclic ring) provided suchring substitution is chemically allowed and results in a stablecompound.

Any of the various carbocyclic and heterocyclic rings and ring systemsdefined herein may be attached to the rest of the compound at any ringatom (i.e., any carbon atom or any heteroatom) provided that a stablecompound results. Suitable 5- or 6-membered heteroaromatic ringsinclude, for example, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl,pyridazinyl, triazinyl, thienyl, furanyl, imidazolyl, pyrazolyl,triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, oxatriazolyl,thiazolyl, isothiazolyl, and thiadiazolyl. The foregoing arerepresentative of heteroaromatics defined by HetB and HetL, and includedin the definitions of HetC and HetD. Suitable heteroaryls consisting ofan aryl fused with a 5-or 6-membered heteroaromatic ring include, forexample, benzopiperidinyl, benzisoxazolyl, benzoxazolyl, chromenyl,quinolinyl, isoquinolinyl, cinnolinyl, and quinazolinyl. The foregoingare representative of fused bicyclic heteroaryls included in thedefinition of HetC and of fused aryl in part (A) of the definition ofR^(J). Suitable 4- to 7-membered saturated heterocyclics include, forexample, azetidinyl, piperidinyl, morpholinyl, thiomorpholinyl,thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl,pyrrolidinyl, imidazolidinyl, piperazinyl, tetrahydrofuranyl,tetrahydrothienyl, pyrazolidinyl, hexahydropyrimidinyl, thiazinanyl,thiazepanyl, thiadiazepanyl, dithiazepanyl, azepanyl, diazepanyl,thiadiazinanyl, tetrahydropyranyl, tetrahydrothiopyranyl, and dioxanyl.The foregoing are representative of saturated heterocyclics defined byHetK and included in the definition of HetD.

A “stable” compound is a compound which can be prepared and isolated andwhose structure and properties remain or can be caused to remainessentially unchanged for a period of time sufficient to allow use ofthe compound for the purposes described herein (e.g., therapeutic orprophylactic administration to a subject).

As a result of the selection of substituents and substituent patterns,certain of the compounds of the present invention can have asymmetriccenters and can occur as mixtures of stereoisomers, or as individualdiastereomers, or enantiomers. All isomeric forms of these compounds,whether isolated or in mixtures, are within the scope of the presentinvention.

As would be recognized by one of ordinary skill in the art, certain ofthe compounds of the present invention can exist as tautomers, such asthe following:

For the purposes of the present invention a reference herein to acompound of Formula I, II, or III is a reference to the compound per se,or to any one of its tautomers per se, or to mixtures of two or moretautomers.

In instances where a hydroxy (—OH) substituent(s) is(are) permitted on aheteroaromatic ring and keto-enol tautomerism is possible, it isunderstood that the substituent might in fact be present, in whole or inpart, in the keto form, as exemplified here for a hydroxypyridinylsubstituent:

Compounds of the present invention having a hydroxy substituent on acarbon atom of a heteroaromatic ring are understood to include compoundsin which only the hydroxy is present, compounds in which only thetautomeric keto form (i.e., an oxo substituent) is present, andcompounds in which the keto and enol forms are both present.

Certain of the compounds of the present invention can exhibit achirality resulting from the presence of bulky substituents that hinderthe otherwise free rotation about a bond. These rotational enantiomersare named atropisomers, and the interconversion can be sufficiently slowto allow for their separation and characterization. See, e.g., J. March,Advanced Organic Chemistry, 4th Edition, John Wiley & Sons, 1992, pp.101-102; and Ahmed et al., Tetrahedron 1998, 13277. For example, certainof the compounds of the present invention in which R⁴ is—C(═O)N(R^(a))R^(b) or —N(R^(a))SO₂R^(b) where at least one of R^(a) andR^(b) is alkyl can have sufficiently hindered rotation along the bondlinking R⁴ to the bicyclic core of the molecule when R⁵ is other than H(e.g., R⁵=alkyl, cycloalkyl, or aryl) to permit separation of theenantiomers using, e.g., column chromatography on a chiral stationaryphase. The present invention includes atropisomers of compounds embracedby Formula I, singly and in mixtures.

The compounds of the present inventions are useful in the inhibition ofHIV integrase (e.g., HIV-1 integrase), the prevention or treatment ofinfection by human immunodeficiency virus (HIV) and the prevention,treatment or the delay in the onset of consequent pathologicalconditions such as AIDS. Preventing AIDS, treating AIDS, delaying theonset of AIDS, or preventing or treating infection by HIV is defined asincluding, but not limited to, treatment of a wide range of states ofHIV infection: AIDS, ARC (AIDS related complex), both symptomatic andasymptomatic, and actual or potential exposure to HIV. For example, thecompounds of this invention are useful in treating infection by HIVafter suspected past exposure to HIV by such means as blood transfusion,exchange of body fluids, bites, accidental needle stick, or exposure topatient blood during surgery.

The compounds of this invention are useful in the preparation andexecution of screening assays for antiviral compounds. For example, thecompounds of this invention are useful for isolating enzyme mutants,which are excellent screening tools for more powerful antiviralcompounds. Furthermore, the compounds of this invention are useful inestablishing or determining the binding site of other antivirals to HIVintegrase, e.g., by competitive inhibition. Thus the compounds of thisinvention are commercial products to be sold for these purposes.

The compounds of the present invention may be administered in the formof pharmaceutically acceptable salts. The term “pharmaceuticallyacceptable salt” refers to a salt which possesses the effectiveness ofthe parent compound and which is not biologically or otherwiseundesirable (e.g., is neither toxic nor otherwise deleterious to therecipient thereof). Suitable salts include acid addition salts whichmay, for example, be formed by mixing a solution of the compound of thepresent invention with a solution of a pharmaceutically acceptable acidsuch as hydrochloric acid, sulfuric acid, acetic acid, trifluoroaceticacid, or benzoic acid. Many of the compounds of the invention carry anacidic moiety, in which case suitable pharmaceutically acceptable saltsthereof can include alkali metal salts (e.g., sodium or potassiumsalts), alkaline earth metal salts (e.g., calcium or magnesium salts),and salts formed with suitable organic ligands such as quaternaryammonium salts. Also, in the case of an acid (—COOH) or alcohol groupbeing present, pharmaceutically acceptable esters can be employed tomodify the solubility or hydrolysis characteristics of the compound.

The term “administration” and variants thereof (e.g., “administering” acompound) in reference to a compound of the invention mean providing thecompound or a prodrug of the compound to the individual in need oftreatment. When a compound of the invention or a prodrug thereof isprovided in combination with one or more other active agents (e.g.,antiviral agents useful for treating HIV infection or AIDS),“administration” and its variants are each understood to includeconcurrent and sequential provision of the compound or prodrug and otheragents.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients, as well as any productwhich results, directly or indirectly, from combining the specifiedingredients.

By “pharmaceutically acceptable” is meant that the ingredients of thepharmaceutical composition must be compatible with each other and notdeleterious to the recipient thereof.

The term “subject” (alternatively referred to herein as “patient”) asused herein refers to an animal, preferably a mammal, most preferably ahuman, who has been the object of treatment, observation or experiment.

The term “effective amount” as used herein means that amount of activecompound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal or human that is beingsought by a researcher, veterinarian, medical doctor or other clinician.In one embodiment, the effective amount is a “therapeutically effectiveamount” for the alleviation of the symptoms of the disease or conditionbeing treated. In another embodiment, the effective amount is a“prophylactically effective amount” for prophylaxis of the symptoms ofthe disease or condition being prevented. The term also includes hereinthe amount of active compound sufficient to inhibit HIV integrase andthereby elicit the response being sought (i.e., an “inhibition effectiveamount”). When the active compound (i.e., active ingredient) isadministered as the salt, references to the amount of active ingredientare to the free acid or free base form of the compound.

For the purpose of inhibiting HIV integrase, preventing or treating HIVinfection or preventing, treating or delaying the onset of AIDS, thecompounds of the present invention, optionally in the form of a salt,can be administered by any means that produces contact of the activeagent with the agent's site of action. They can be administered by anyconventional means available for use in conjunction withpharmaceuticals, either as individual therapeutic agents or in acombination of therapeutic agents. They can be administered alone, buttypically are administered with a pharmaceutical carrier selected on thebasis of the chosen route of administration and standard pharmaceuticalpractice.

The compounds of the invention can, for example, be administered orally,parenterally (including subcutaneous injections, intravenous,intramuscular, intrasternal injection or infusion techniques), byinhalation spray, or rectally, in the form of a unit dosage of apharmaceutical composition containing an effective amount of thecompound and conventional non-toxic pharmaceutically-acceptablecarriers, adjuvants and vehicles. Liquid preparations suitable for oraladministration (e.g., suspensions, syrups, elixirs and the like) can beprepared according to techniques known in the art and can employ any ofthe usual media such as water, glycols, oils, alcohols and the like.Solid preparations suitable for oral administration (e.g., powders,pills, capsules and tablets) can be prepared according to techniquesknown in the art and can employ such solid excipients as starches,sugars, kaolin, lubricants, binders, disintegrating agents and the like.Parenteral compositions can be prepared according to techniques known inthe art and typically employ sterile water as a carrier and optionallyother ingredients, such as a solubility aid. Injectable solutions can beprepared according to methods known in the art wherein the carriercomprises a saline solution, a glucose solution or a solution containinga mixture of saline and glucose. Further description of methods suitablefor use in preparing pharmaceutical compositions of the presentinvention and of ingredients suitable for use in said compositions isprovided in Remington's Pharmaceutical Sciences, 18^(th) edition, editedby A. R. Gennaro, Mack Publishing Co., 1990.

The compounds of this invention can be administered orally in a dosagerange of about 0.001 to about 1000 mg/kg of mammal (e.g., human) bodyweight per day in a single dose or in divided doses. One preferreddosage range is about 0.01 to about 500 mg/kg body weight per day orallyin a single dose or in divided doses. Another preferred dosage range isabout 0.1 to about 100 mg/kg body weight per day orally in single ordivided doses. For oral administration, the compositions can be providedin the form of tablets or capsules containing about 1.0 to about 500milligrams of the active ingredient, particularly 1, 5, 10, 15, 20, 25,50, 75, 100, 150, 200, 250, 300, 400, and 500 milligrams of the activeingredient for the symptomatic adjustment of the dosage to the patientto be treated. The specific dose level and frequency of dosage for anyparticular patient may be varied and will depend upon a variety offactors including the activity of the specific compound employed, themetabolic stability and length of action of that compound, the age, bodyweight, general health, sex, diet, mode and time of administration, rateof excretion, drug combination, the severity of the particularcondition, and the host undergoing therapy. As an example, the titlecompound of Example 12 below can be administered to adult humans in theform of an amorphous Na salt in a neat drug-filled capsule in an amountof from about 5 mg to about 800 mg (e.g., 400 mg) twice/day. As anotherexample, the crystalline compound of Example 13 or an amorphous Na saltthereof can be administered to adult humans in the same fashion.

As noted above, the present invention is also directed to use of the HIVintegrase inhibitor compounds of the present invention with one or moreagents useful in the treatment of HIV infection or AIDS. For example,the compounds of this invention may be effectively administered, whetherat periods of pre-exposure and/or post-exposure, in combination witheffective amounts of one or more HIV/AIDS antivirals, immunomodulators,antiinfectives, or vaccines useful for treating HIV infection or AIDS,such as those disclosed in Table I of WO 01/38332 or in the Table in WO02/30930. Suitable HIV/AIDS antivirals for use in combination with thecompounds of the present invention include, for example, HIV proteaseinhibitors (e.g., indinavir, atazanavir, lopinavir optionally withritonavir, saquinavir, or nelfinavir), nucleoside HIV reversetranscriptase inhibitors (e.g., abacavir, lamivudine (3TC), zidovudine(AZT), or tenofovir), and non-nucleoside HIV reverse transcriptaseinhibitors (e.g., efavirenz or nevirapine). It will be understood thatthe scope of combinations of the compounds of this invention withHIV/AIDS antivirals, immunomodulators, anti-infectives or vaccines isnot limited to the foregoing substances or to the list in theabove-referenced Tables in WO 01/38332 and WO 02/30930, but includes inprinciple any combination with any pharmaceutical composition useful forthe treatment of AIDS. The HIV/AIDS antivirals and other agents willtypically be employed in these combinations in their conventional dosageranges and regimens as reported in the art, including, for example, thedosages described in the Physicians' Desk Reference, 57^(th) edition,Thomson PDR, 2003. The dosage ranges for a compound of the invention inthese combinations are the same as those set forth above.

Abbreviations used in the instant specification, particularly the in theSchemes and Examples, include the following: Ac=acetyl; AIDS=acquiredimmunodeficiency syndrome; AIBN=2,2-azobisisobutyronitrile; ARC=AIDSrelated complex; BOC or Boc=t-butyloxycarbonyl;BOP=benzotriazol-1-yloxytris-(dimethylamino)phosphonium;DABCO=1,4-diazabicyclo[2.2.2]octene; DCM=dichloromethane;DME=1,2-dimethoxyethane; DMF=N,N-dimethylformamide;DMPU=1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (orN,N′-dimethylpropyleneurea); DMSO=dimethylsulfoxide; ES MS=electrospraymass spectroscopy; Et=ethyl; EtOAc=ethyl acetate; HIV=humanimmunodeficiency virus; HOAc=acetic acid;HOAT=1-hydroxy-7-azabenzotriazole; HPLC=high performance liquidchromatography; HMPA=hexamethylphosphoramide; IPAc=isopropyl acetate;LC=liquid chromatography; LHMDS=lithium hexamethyldisilazide;mCPBA=meta-chloroperbenzoic acid; Me=methyl; MeOH=methanol; Ms=mesylate;MTBE=methyl tert-butyl ether; NBS=N-bromosuccinimide; NMR=nuclearmagnetic resonance; t-Bu=tert-butyl; TEA=triethylamine;TFA=trifluoroacetic acid; THF=tetrahydrofuran; Ts=tosyl.

The compounds of the present invention can be readily prepared accordingto the following reaction schemes and examples, or modificationsthereof, using readily available starting materials, reagents andconventional synthesis procedures. In these reactions, it is alsopossible to make use of variants which are themselves known to those ofordinary skill in this art, but are not mentioned in greater detail.Furthermore, other methods for preparing compounds of the invention willbe readily apparent to the person of ordinary skill in the art in lightof the following reaction schemes and examples. Unless otherwiseindicated, all variables are as defined above.

Scheme 1 depicts a method for preparing5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate intermediates usefulfor making compounds of the present invention. In the scheme, lactam 1-1can be alkylated with an appropriate alkyl halide to give 1-2, usingmethods as described in Jerry March, Advanced Organic Chemistry, 3rdedition, John Wiley & Sons, 1985, pp. 377-379. Piperidin-2-one 1-2 canbe converted to the corresponding dihydropyridinone compound 1-5following the two step procedure set forth in Meyers et al., Tett. Lett.1995, 36: 7051-7054, wherein the lactam can be treated with base andmethyl benzene sulfinate to give intermediate 1-4, which can then betreated by heating in a high boiling solvent (e.g., toluene) andoptionally in the presence of base to effect the elimination to 1-5.Separately, oxazoles of the type 1-9 can readily be prepared byacylating amino acid ester 1-6 with an oxylate ester 1-7 in the presenceof base to afford acylated compound 1-8, which can then be cyclized anddehydrated (using, e.g., P₂O₅) in the manner described in Krapcho et al.J. Heterocyclic Chem. 1995, 32, 1693-1702 to afford oxazole 1-9.Diels-Alder reaction of 1-9 and 1-5, optionally in the presence of wateror an acid (preferably in the presence of water), will then provide thedesired napthyridine intermediate 1-10.

Scheme 2 depicts a method for preparing naphthyridine carboxylates andcarboxamides embraced by the present invention from naphthyridineintermediate 1-10, wherein the intermediate 1-10 is contacted with asuitable oxidizing agent (e.g., hydrogen peroxide or mCPBA) to obtainN-oxide 2-1, which can then be treated as described Suzuki et al. J.Med. Chem. 1992, 35, 4045-4053 with acetic anhydride to effect therearrangement to the O-acylated intermediate, and then treated with anucleophile (e.g., an alkoxide such as NaOMe) to afford the desireddioxohexahydro-2,6-naphthyridine-1-carboxylate 2-2. The alkylcarboxylate 2-2 can then be further treated with an appropriate amineand trimethylaluminum in the manner described in Evans et al., J. Am.Chem. Soc. 1990, 112: 7001 to give the desired alkyl carboxamide 2-3.

Scheme 3 depicts an alternative method for preparing naphthyridinecarboxamides 2-3 and analogs in which the R⁵ substituent is other thanH. The intermediate 2-2 can be alkylated with an alkylating agent (e.g.,an alkyl halide or an alkyl sulfate such as dimethyl sulfate) using asuitable base (e.g., (i) an alkali metal carbonate such as K₂CO₃ orCs₂CO₃, (ii) an alkali metal hydride such as NaH, (iii) a metal alkoxidesuch as Mg(OMe)₂, or (iv) the combination of (i) and (iii) in successivesteps) to give a mixture of N- and O-alkylated products 3-1 and 3-2. Asimilar method using alkali metal carbonates is described in T. Ukitaet. al., Chem. Pharm. Bull. 2000, 48 (4): 589-591. Analogs possessing anon-H R⁵ substituent can also be prepared by hydrolysis of theN-alkylated product 3-1 with a nucleophile such as hydroxide to affordthe acid 3-3, followed by conversion to the acid chloride 3-4 using asuitable agent like thionyl chloride or oxalyl chloride/catalytic DMF,similar to the method described in Jerry March, Advanced OrganicChemistry, 3rd edition, John Wiley & Sons, 1985, pp. 388. The acid 3-3can be coupled with an amine using a peptide coupling reagent such asBOP, or, alternatively, the acid chloride 3-4 can be treated directlywith an amine to give the amide. The O-alkylated groups can then beremoved under acidic conditions (e.g., using a strong acid like HBr in a5 suitable solvent like acetic or propionic acid, or using p-toluenesulfonic acid, or a reagent like BBr₃) to give 3-5, similar to themethod described in Jerry March, Advanced Organic Chemistry, 3rdedition, John Wiley & Sons, 1985, pp. 384. A similar sequence ofhydrolysis, acid chloride formation, coupling and de-protection,starting from the bis-O-alkylated compound 3-2, can allow thepreparation of compounds 2-3.

Scheme 4 depicts a method for preparing compounds of the invention inwhich the R⁴ group is linked to the parent template via anitrogen-carbon bond. Acid chloride 34 can be treated with sodium azideto give the acyl azide, which will undergo Curtius rearrangementfollowed by hydrolysis to the amine 4-2, similar to the method describedin R. J. Borchis et. al. J. Med. Chem. (1981), 24, 1518-1521. The aminemay then be acylated or sulfonylated with the appropriate agent like anacyl or sulfonyl anhydride or acyl or sulfonyl chloride to give the monoor bis N-acyl or N-sulfonylated intermediate, which can then beconverted to product 4-3 by using a suitable nucleophile like sodiummethoxide or sodium hydroxide. The amine can further be modified byalkylation with a suitable alkyl halide under 5 the influence of a base(e.g., Cs₂CO₃ or K₂CO₃, using a method similar to that described in A.Nadin, et. al. J. Org. Chem. (2003), 68(7), 2844-2852, to give compounds4-4. The O-alkyl group can then be removed with a strong acid like HBrto give 4-5.

Scheme 5 depicts an alternative sequence of transformations similar tothose described in the above schemes. Starting with the intermediate1-10, O-alkylation, hydrolysis of the ester to the acid, acid chlorideformation, acyl azide formation, Curtius rearrangement and hydrolysisgive the intermediate 5-1, which can be derivatized with various acyl orsulfonyl halides, and then alkylated to give 5-2. N-oxide formation,similar to that described in M. Adamczyk, Tetrahedron (2002) 58,6951-6963, followed by rearrangement in acetic anhydride and hydrolysiswill give 5-4, and cleavage of the 0-alkyl group in acid will afford5-5.

Scheme 6 depicts a route to compounds containing a double bond in the“a” position. These analogs can be prepared from treatment of anintermediate like 1-10 with a brominating agent (e.g., NBS) followed byelimination to give the double bond, similar to the method described inJerry March, Advanced Organic Chemistry, 3rd edition, John Wiley & Sons,1985, pp. 914. The intermediate 6-1 can then be taken through a seriesof transformations as previously outlined to give products 6-2 and 6-3.

Scheme 7 shows methods that can be used to prepare analogs in which R⁴is attached by a carbon-carbon bond. The amine 4-2 or 5-1 can beconverted to the halide 7-1, using methods described in A. Bouillon et.al. Tetrahedron 58 (14) 2885-2890 (2002), which will allow forcarbon-carbon bond formation. Treatment of the halide with a palladiumcatalyst and vinyl halide, for example, using methods developed by R. F.Heck (M. Schlosser, Organometallics in Synthesis, a Manual 2^(nd) ed.John Wiley and Sons, Ltd. NY 2002, pp 1169) can provide intermediate7-2, which can be reduced to the alkyl analog 7-3. Similarly, treatmentof the halide with an organometallic catalyst such as zinc or palladiumand an aryl or heteroaryl boronic acid, an aryl or heteroaryl tinreagent, or an aryl and heteroaryl halide will afford the product 7-4Such transformations are well known in the art and are described, forexample, in J. J. Li, G. W. Gribble Palladium in Heterocyclic Chemistry,Pergamon Press NY 2000. Compounds 7-3 and 7-4 can then be taken throughthe sequence of steps elaborated in previous schemes to affordadditional compounds of the present invention.

Scheme 8 depicts a method for preparing analogs with R¹ substituentsfrom starting substrate 8-1 with a removable R* group. Substrate 8-1,containing an R* functional group (i.e., a group which is readilyremovable from an amide moiety, such as p-methoxybenzyl, 3,4- or2,4-bismethoxybenzyl, allyl, or tosyl), can be prepared by coupling asuitable acid 3-3 or acid chloride 3-4 with an amine (see Scheme 3), andcan be de-protected with a strong acid like p-toluene sulfonic acid in amanner similar to the method described in W. M. Kan et. al., Tetrahedron2000, 44: 1039-1041 to give intermediate 8-2. Deprotected compound 8-2can then be bis-alkylated with a suitable alkyl halide using a base(e.g., NaH) to give the N,O-alkylated intermediate 8-3. Removal of theO-alkyl group with strong acid (e.g., HBR in a solvent such as acetic orpropionic acid) will then afford the product 8-4.

Scheme 9 depicts an alternative method for preparing naphthyridinecarboxamide analog intermediate 8-1 embraced by the present invention inwhich the amide substituent is incorporated early in the reactionscheme, and in which the R* substituent (defined in Scheme 8) is used toallow variation of R¹ at a late stage in the synthesis. Startingmaterial 9-1 can be prepared in a manner similar to that used for 1-10,incorporating the removable group in the initial alkylation step asdescribed for 1-2. The phenolic group in 9-1 can be protected with asuitable alkyl protecting group (e.g., an R⁵ group as defined hereinother than H) followed by hydrolysis with a nucleophile such ashydroxide to afford 9-2. Protection can be accomplished, for example, bytreatment with a diazomethane reagent (e.g., TMS diazomethane) insolvent (e.g., chloroform) or by alkylation with an alkylating agent(e.g., by contact with an alkyl halide or an alkyl sulfate such asdimethyl sulfate) in the presence of a suitable base (e.g., an alkalimetal carbonate such as K₂CO₃ or Cs₂CO₃ or an alkali metal hydride suchas NaH) in a solvent such as DMSO or methylene chloride. The acid 9-2can be coupled with an amine using a peptide coupling reagent such asEDC to obtain 9-3. The intermediate 9-3 can then be treated with asuitable oxidizing agent (e.g., mCPBA or peracetic acid) to obtain theN-oxide, which can then be treated as described Suzuki et al. J. Med.Chem. 1992, 35, 4045-4053 with acetic anhydride to effect therearrangement to the O-acylated intermediate, and then treated with anucleophile (e.g., an alkoxide such as NaOMe) to afford thedioxohexahydro-2,6-naphthyridine-1-carboxylate 9-4. Intermediate 9-4 canbe alkylated with an alkylating agent (e.g., an alkyl halide or an alkylsulfate such as dimethyl sulfate) using a suitable base (e.g., an alkalimetal carbonate such as K₂CO₃ or Cs₂CO₃, an alkali metal hydride such asNaH, or a metal alkoxide such as Mg(OMe)₂) in a solvent like DMSO togive a mixture of N- and O-alkylated products 8-1 and 9-5. A similar useof alkali metal carbonates is described in T. Ukita, et. al. Chem.Pharm. Bull. 2000, 48 (4) 589-591.

When R* is a benzyl analog containing a chloro in the benzyl ring thechloro can be removed via catalytic dechlorination (e.g., in thepresence of 10% palladium on charcoal in methanol) under an atmosphereof hydrogen using conditions similar to those described in M.Freifelder, Catalytic Hydrogenation in Organic Synthesis Procedures andCommentary, John Wiley & Sons, 1978, pp. 121. See, e.g., Examples 69 and70.

When R* is a benzyl analog, the benzyl can be iodinated with a suitableiodinating reagent (e.g., N-iodosuccinimide) in the presence of an acid(e.g., trifluoromethanesulfonic acid or TFA) in a manner similar to thatdescribed in Olah et al., J. Org. Chem. 1999, 3194, or Castanet et al.,Tetrahedron. Lett. 2002, 5047. See, e.g., Examples 71 and 72.

Scheme 10 depicts an alternative method for preparing naphthyridinecarboxamide analogs embraced by the present invention in which the R⁵substituent is other than H, starting from naphthyridine intermediate10-1. Hydrolysis of the pyridine 10-1 with a nucleophile such ashydroxide can afford the acid 10-2, which can be coupled with an amineusing a peptide coupling reagent such as BOP to afford amide 10-3.Alternatively, 10-2 can be converted to the acid chloride using asuitable agent like thionyl chloride or oxalyl chloride/catalytic DMF,similar to the method described in Jerry March, Advanced OrganicChemistry, 3rd edition, John Wiley & Sons, 1985, pp. 388, and the acidchloride treated directly with an amine to give the amide 10-3. Theintermediate 10-3 can then be treated with a suitable oxidizing agent(e.g., mCPBA or peracetic acid) to obtain the N-oxide 10-4, which canthen be treated as described Suzuki et al. J. Med. Chem. 1992, 35,40454053 with acetic anhydride to effect the rearrangement to theO-acylated intermediate, and then treated with a nucleophile (e.g., analkoxide such as NaOMe) to afford the desireddioxohexahydro-2,6-naphthyridine-1-carboxylate 10-5. Intermediate 10-5can be alkylated with an alkylating agent (e.g., an alkyl halide or analkyl sulfate such as dimethyl sulfate) using a suitable base (e.g., analkali metal carbonate such as K₂CO₃ or Cs₂CO₃, an alkali metal hydridesuch as NaH, or a metal alkoxide such as Mg(OMe)₂) in a solvent likeDMSO to give a mixture of N- and O-alkylated products 10-6 and 10-7. Asimilar use of alkali metal carbonates is described in T. Ukita, et. al.Chem. Pharm. Bull. 2000, 48 (4) 589-591.

Scheme 11 depicts a method for preparation of N-aryl or N-heterocyclylnapthyridine carboxamides (see, e.g., Examples 25 to 53). Theintermediate 11-1 can be prepared as described in Scheme 3 (see alsoSteps 1 to 6 of Example 12). The hydroxyl group on 11-1 can be protectedas alkyl ether by treatment with a base (e.g., cesium carbonate, sodiumhydride, or sodium bis(trimethyl)silylamide), followed by reaction withan alkylating reagent such as methyl iodide, benzyl bromide, usingmethods similar to those described in T. W. Greene & P. G. M. Wuts,Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons,1999, p. 246. The resultant napthyridine intermediate 11-2 can then beconverted to the corresponding napthyridinone intermediate 11-3 in asequence similar to that described in Steps 1 to 5 of Example 13.Napthyridinone 11-3 can then be N-arylated with an appropriate aryl orheterocyclyl boronic acid in the presence of a catalyst such ascopper(II) acetate (see Lam et al, Tetrahedron Lett. 1998, p. 2941, andreferences cited therein) and the resulting N-arylated compound treatedwith HBr in acetic acid or boron tribromide (see Scheme 2) to remove theether protecting group and thereby provide 11-4.

Scheme 12 depicts a method for the preparation of N-aminoethylnapthyridine carboxamides (see, e.g., Examples 66 to 68). Theintermediate 12-1 can be alkylated with a dihaloalkane (exemplified bybromo-2-chloroethane in the scheme) using established alkylationconditions (e.g., in DMSO in the presence of magnesium methoxide asdescribed in of Scheme 10) to provide the intermediate alkylationproduct 12-2a. Treatment of 12-2a with a suitable secondary amine in thepresence of sodium iodide provides 12-3. Similarly, 12-1 can be reactedwith a Boc-protected haloalkyl secondary amine (exemplified by1-bromo-2-N-Boc-N-alkyl-aminoethane in the scheme) to provide 12-2b,which can be treated with acid (e.g., HCl in dioxane) to provide thedesired 12-4 (see T. W. Greene & P. G. M. Wuts, Protective Groups inOrganic Synthesis, 3rd edition, John Wiley & Sons, 1999, p. 520).

Scheme 13 depicts a method for preparation of napthyridine sulfonamides(see, e.g., Examples 73 to 76). The carboxylic group in intermediate13-1, which can be prepared as described in Scheme 3, can be convertedto the corresponding tert-butyl carbamate 13-2 via a Curtiusrearrangement in the manner described in J. March, Advanced OrganicChemistry, 3rd edition, John Wiley & Sons, 1992, p. 1091 (e.g., acid13-1 can be treated with diphenylphosphoryl azide in the presence ofanhydrous tert-butanol to afford carbamate 13-2). Carbamate 13-2 canthen be treated with base (e.g., as sodium hydride or sodiumbis(trimethyl)silylamide), followed by contact with a sulfonylationreagent (e.g., an alkane sulfonyl chloride) to provide an intermediatesulfonylated carbamate, which can be transformed to the correspondingsulfonamide 13-3 by treatment with acid (e.g., TFA) in a manner similarto the 5 conditions described in T. W. Greene & P. G. M. Wuts,Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons,1999, p. 520. Treatment of 13-3 with a base (e.g., sodium hydride orsodium bis(trimethyl)silyl-amide), followed by alkylation with asuitable reagent (e.g., an alkyl halide such as methyl iodide) and thenby removal of the ether protecting group (see Schemes 2 and 11) toafford the desired 13-4.

Scheme 14 depicts the preparation of bromo compounds of the invention,wherein the carboxylic acid intermediate 14-1 (Scheme 9) is converted tothe corresponding acid chloride by treatment with a suitable agent(e.g., oxalyl chloride or thionyl chloride) and the resulting acidchloride is converted to the corresponding bromide 14-2 via a Bartondecarboxylative bromination as described in Barton et al, TetrahedronLett. 1985, 5939 (e.g., with a mixture of bromotrichloro-methane and2-pyridinethiol-N-oxide in the presence of AIBN). The bromide 14-2 canthen be converted to the corresponding napthyridinone intermediate in asequence similar to that described in Scheme 3. Subsequent removal ofthe ether protecting group (see description in Scheme 2 or Scheme 11)affords the desired 14-3. N-alkylation of 14-3 provides 14-4. Catalyticdebromination of 14-3 and 14-4 (e.g., in the presence of 10% palladiumon charcoal in methanol under an atmosphere of hydrogen similar toconditions described in M. Freifelder, Catalytic Hydrogenation inOrganic Synthesis Procedures and Commentary, John Wiley & Sons, 1978, p.121) will afford analogs without a substituent in the 5-position of thenaphthyridine ring.

Scheme 15 depicts the preparation of alkylated products from a startingbromide, wherein bromide 14-4 is treated with an appropriate vinylstannane in the presence of a palladium catalyst to provide thecorresponding vinyl napthyridine intermediate 15-1. Hydrogenation orcyclopropanation of this intermediate, followed by removal of the etherprotecting group, will afford the corresponding desired alkylsubstituted napthyridine 15-2 and cyclopropane substituted napthyridine15-3.

Compounds of the present invention having aryl, heteroaryl, or saturatedheterocyclyl groups in the naphthyridine ring can be prepared bytreatment of 14-4 with a saturated heterocycle or with anaryl/heteroaryl boronic acid or ester in the presence of a suitableligand-complexed metal catalyst. Scheme 16 is illustrative, wherein thedesired arylated analog 16-1 is obtained by treating 14-4 with an arylboronic acid in the presence of a palladium catalyst (e.g.,tetrakis(triphenylphosphine)-palladium(0)). Suitable chemistries aredescribed in Angew Chem. Intl. 2004, 1871; Org. Lett. 2003, 793; andTetrahedron Lett. 2004, 3305.

The present invention also includes a process (alternatively referred toherein as “Process P1” or the “P1 process”) for preparing a compound ofFormula IV:

which comprises:

(B) contacting a compound of Formula V:

with a Grignard salt of an amine of Formula VI:HN(R^(V))R^(W)  (VI)to obtain Compound IV; wherein:bond

in the ring is a single bond or a double bond;R¹ is —C₁₋₆ alkyl substituted with R^(J), wherein R^(J) is:

-   -   (A) aryl or aryl fused to a 5- or 6-membered heteroaromatic ring        containing from 1 to 4 heteroatoms independently selected from        N, O and S, wherein the aryl or fused aryl is:        -   (a) optionally substituted with from 1 to 5 substituents            each of which is independently:            -   (1) —C₁₋₆ alkyl,            -   (2) —C₁₋₆ alkyl substituted with —O—C₁₋₆ alkyl, —O—C₁₋₆                haloalkyl, —NO₂, —N(R^(a))R^(b), or —S(O)_(n)R^(a),            -   (3) —C₁₋₆ haloalkyl,            -   (4) —O—C₁₋₆ alkyl,            -   (5) halogen,            -   (6) —C(═O)N(R^(a))R^(b), or            -   (7) —SO₂R^(a), and        -   (b) optionally substituted with 1 or 2 substituents each of            which is independently:            -   (1) phenyl,            -   (2) benzyl, or            -   (3) —HetB;                -   wherein each HetB is a 5- or 6-membered                    heteroaromatic ring containing from 1 to 4                    heteroatoms independently selected from N, O and S,                    wherein the heteroaromatic ring is optionally                    substituted with from 1 to 4 substituents each of                    which is independently halogen, —C₁₋₆ alkyl, —C₁₋₆                    haloalkyl, —O—C₁₋₆ alkyl, or —O—C₁₋₆ haloalkyl; or    -   (B) a 5- or 6-membered heteroaromatic ring containing from 1 to        4 heteroatoms independently selected from N, O and S; wherein        the heteroaromatic ring is        -   (i) optionally substituted with from 1 to 4 substituents            each of which is independently halogen, —C₁₋₆ alkyl, —C₁₋₆            haloalkyl, —O—C₁₋₆ alkyl, or —O—C₁₋₆ haloalkyl, and        -   (ii) optionally substituted with 1 or 2 substituents each of            which is independently aryl or —C₁₋₆ alkyl substituted with            aryl;            R² and R³ are each independently —H or —C₁₋₆ alkyl;            R⁵ is:    -   (1) —C₁₋₆ alkyl,    -   (2) —C₃₋₈ cycloalkyl optionally substituted with from 1 to 4        substituents each of which is independently —C₁₋₆ alkyl or        —O—C₁₋₆ alkyl,    -   (3) —C₁₋₆ alkyl substituted with C₃₋₈ cycloalkyl, wherein the        cycloalkyl is optionally substituted with from 1 to 4        substituents each of which is independently —C₁₋₆ alkyl or        —O—C₁₋₆ alkyl,    -   (4) —C₁₋₆ alkyl substituted with aryl, wherein the aryl is        optionally substituted with from 1 to 5 substituents each of        which is independently —C₁₋₆ alkyl, —C₁₋₆ alkylene-O—C₁₋₆ alkyl,        or halogen, or    -   (5) —C₁₋₆ alkyl substituted with a 5- or 6-membered        heteroaromatic ring containing from 1 to 4 heteroatoms        independently selected from N, O and S, wherein the        heteroaromatic ring is optionally substituted with from 1 to 4        substituents each of which is independently —C₁₋₆ alkyl;        R^(T) is —C₁₋₆ alkyl;        R^(V) and R^(W) are each independently —C₁₋₆ alkyl or R^(V) and        R^(W) together with the N atom to which they are both attached        form a 4- to 6-membered saturated heterocyclic ring optionally        containing a heteroatom in addition to the nitrogen attached to        R^(V) and R^(W) selected from N, O, and S, where the S is        optionally oxidized to S(O) or S(O)₂, and wherein the saturated        heterocyclic ring is optionally substituted with 1 or 2        substituents each of which is independently a C₁₋₆ alkyl group;        each aryl is independently phenyl, naphthyl, or indenyl;        each R^(a) is independently H or C₁₋₆ alkyl; and        each R^(b) is independently H or C₁₋₆ alkyl.

Process P1 can produce Compound IV from Compound V in good yield withoutprotecting the 4-hydroxy group. The P1 process is exemplified in Step 8of Example 91, wherein the protection and deprotection steps included inthe process set forth in Example 12 are avoided.

The Grignard salt employed in the P1 process is typically ahalomagnesium salt of amine VI. The halomagnesium salt of amine VI ispreferably a chloromagnesium salt or a bromomagnesium salt of amine VI,and is more preferably a chloromagnesium salt of amine VI (i.e.,ClMgN(R^(V))R^(W)).

Representative amines of Formula VI which can be employed in the P1process include dimethylamine, diethylamine, isopropylethylamine,azetidine, pyrrolidine, piperidine, piperazine, 4-methylpiperazine,morpholine, and thiomorpholine.

The contacting step B of the P1 process is suitably conducted in anaprotic solvent. As used herein, the term “solvent” refers to an organicsubstance which is a chemically inert liquid under the reactionconditions and which will dissolve or suspend the reactants in such amanner as to bring the reactants into contact and permit the reaction toproceed.

Aprotic solvents suitable for use in the present invention include thoseselected from the group consisting of alkanes, cycloalkanes, halogenatedalkanes, halogenated cycloalkanes, aromatic hydrocarbons, alkylatedaromatic hydrocarbons, halogenated aromatic hydrocarbons, alkylated andhalogenated aromatic hydrocarbons, ethers, polyalkylphosphoramides,N,N′-dialkylalkyleneureas, and mixtures thereof. In this context, a“halogenated” compound or substance is a compound or substancecontaining one or more C—H bonds wherein one or more of the hydrogenshave been replaced with halogen. A class of solvents suitable for use inthe P1 process consists of the solvents selected from the groupconsisting of C₁₋₁₀ linear and branched alkanes, C₁₋₁₀ linear andbranched halogenated alkanes, C₅₋₁₀ cycloalkanes, halogenated C₅₋₁₀cycloalkanes, benzene, naphthalene, mono- and di- and tri-C₁₋₆ alkylsubstituted benzenes, halogenated benzenes, halogenated mono- and di-and tri-C₁₋₆ alkyl substituted benzenes, dialkyl ethers wherein eachalkyl is independently a C₁₋₆ alkyl, C₁₋₆ linear and branched alkanessubstituted with two —O—C₁₋₆ alkyl groups (which are the same ordifferent), C₄-C₈ cyclic ethers and diethers, phenyl C₁₋₄ alkyl ethers,diethylene glycol di(C₁₋₄ alkyl)ethers, hexa (C₁₋₆ alkyl)phosphoramides,N,N′-di-(C₁₋₆ alkyl)ethyleneureas, and N,N′-di-(C₁₋₆alkyl)propyleneureas.

Representative examples of aprotic solvents suitable for use as asolvent in the P1 process include the following: pentane (individualisomers and mixtures thereof), hexane (individual isomers and mixturesthereof), heptane (individual isomers and mixtures thereof),cyclopentane, cyclohexane, cycloheptane, carbon tetrachloride,chloroform, methylene chloride, 1,2-dichloroethane,1,1,2-trichloroethane, 1,1,2,2-tetrachloroethane, chlorocyclopentane,chlorocyclohexane, benzene, toluene, o- and m- and p-xylene, xylenemixtures, ethylbenzene, chlorobenzene, bromobenzene, o-chlorotoluene,2,4-dichlorotoluene, 2,4,6-trichlorotoluene, ethyl ether, MTBE, THF,dioxane, 1,2-dimethoxyethane, HMPA, and DMPU.

In one embodiment of the P1 process, the contacting comprises addingCompound V to the Grignard salt of amine VI dissolved or suspended inthe aprotic solvent to form a reaction mixture and ageing the reactionmixture. The Grignard salt can be prepared, for example, by adding amineVI dissolved or suspended in a first aprotic solvent to a solution of analkylmagnesium halide (e.g., a C₁₋₄ alkylmagnesium chloride or bromide)in a second aprotic solvent that is the same or different from the firstaprotic solvent. The addition can suitably be conducted with agitation(e.g., stirring) at a temperature at or below about 0° C. (e.g., fromabout −50 to about 0° C., or from about −10 to about 0° C.). Theresulting admixture (either a solution or suspension) can then be agedwith agitation for a time sufficient to effect formation of the aminesalt, after which Compound V, typically dissolved or suspended in athird aprotic solvent that is the same or different from the first andsecond solvents, can be charged to the admixture (either maintained at atemperature below about 0° C.—e.g., from about −10 to about 0° C.—orwarmed to a temperature in a range of from about 0 to about 25° C.) toprovide a reaction mixture, and the resulting reaction mixture is ageduntil the desired degree of conversion of Compound V is achieved oruntil conversion is complete.

As used herein, the term “ageing” and variants thereof (e.g., “aged”)refer to maintaining the reactants in a given reaction or treatment stepin contact for a time and under conditions effective for achieving thedesired degree of conversion.

Process P1 can be conducted at any temperature at which the reactionforming Compound IV can be detected. The reaction (i.e., the contacting)can suitably be conducted at a temperature in a range of from about 40to about 40° C., is typically conducted at a temperature in a range offrom about −20 to about 25° C., and is more typically conducted at atemperature in a range of from about −10 to about 0° C.

The Grignard salt of amine VI can be employed in any proportion withrespect to Compound V which results in the formation of at least some ofthe desired compound of Formula IV, but the Grignard salt is typicallyemployed in a proportion which, under the reaction conditions (e.g.,temperature) employed, can optimize conversion of Compound V to CompoundIV. The Grignard salt is suitably employed in an amount in a range of atleast about 2 equivalents (e.g., from about 2 to about 10 equivalents)per equivalent of Compound V, is typically employed in an amount in arange of from about 3 to about 6 equivalents per equivalent of CompoundV, and is more typically employed in an amount in a range of from about4 to about 5 equivalents per equivalent of Compound V.

An embodiment of the P1 process is the process as originally definedabove, wherein the compound of Formula IV is a compound of Formula IV-A:

the compound of Formula V is a compound of Formula V-A:

the Grignard salt is a Grignard salt of dimethylamine; X¹ is: (1) —H,(2) bromo, (3) chloro, (4) fluoro, or (5) methoxy; X² is: (1) —H, (2)bromo, (3) chloro, (4) fluoro, (5) methyl, (6) methoxy, (7) —CF₃, or (8)—OCF₃; and R⁵ is —C₁₋₄ alkyl.

Additional embodiments of the P1 process include the process as justdescribed in the preceding embodiment incorporating one or more of thefeatures (i) to (v) as follows:

(i) Compound IV-A is

and Compound V-A is

(ii) the contacting is conducted in an aprotic solvent selected from thegroup consisting of an alkane, a cycloalkane, a halogenated alkane, ahalogenated cycloalkane, an aromatic hydrocarbon, an alkylated aromatichydrocarbon, a halogenated aromatic hydrocarbon, an alkylated andhalogenated aromatic hydrocarbon, an ether, a polyalkyl phosphoramide,an N,N′-dialkylalkyleneurea, and mixtures thereof;

(iii) the Grignard salt is ClMg(CH₃)₂;

(iv) the contacting is conducted at a temperature in a range of fromabout −20 to about 25° C. (e.g., in a range of from about −10 to about0° C.); and

(v) the Grignard salt is employed in an amount of at least about 2equivalents (e.g., in an amount in a range of from about 2 to about 10equivalents, or from about 3 to about 6 equivalents, or from about 4 toabout 5 equivalents) per equivalent of Compound V-A.

Another embodiment of Process P1 is the process as originally set forthabove or as described in a preceding embodiment, which furthercomprises: (C) recovering Compound IV from the reaction medium. CompoundIV can be recovered, for example, by quenching the reaction mixture withan aqueous solution of a mineral acid (e.g., aqueous HCl), separatingthe resulting organic layer (i.e., the aprotic solvent medium containingthe desired product), and removing in whole or in part the volatilesolvent from the organic layer using heat or a vacuum or both to obtainCompound IV either directly or by precipitation from the concentratedorganic layer and separation of the precipitate by filtration.

Still another embodiment of the P1 Process is the process as originallyset forth above which further comprises:

(A) treating a compound of Formula IX:

with (i) a tertiary amine base in the presence of a lithium salt or (ii)an alkoxide base, to obtain a compound of Formula V; wherein one ofbonds

and

is a single bond and the other is a double bond; R^(T)* is C₁₋₆ alkyl(where R^(T) and R^(T)* can be the same or different alkyl groups); andall other variables are as originally defined in the P1 process. In anaspect of this embodiment, Compound IX is a compound of Formula IX-A:

Compound V is a compound of Formula V-A as defined above; R^(T) andR^(T)* are each independently C₁₋₄ alkyl; and R⁵, X¹ and X² are each asdefined in Compound V-A above. This embodiment of the P1 process (i.e.,the embodiment including Steps A and B) is alternatively referred toherein as “Process P1a” or the “P1a process”.

The tertiary amine bases suitable for use in the P1a process includetrimethylamine, triethylamine, tri-n-butylamine, ethyl-diisopropylamine,N,N-dimethylaniline, N,N-dimethyl-benzylamine, pyridine, picoline,N-methylpiperidine, N-methylmorpholine, 4-N,N-dimethylaminopyridine(DMAP), 1,4-diazabicyclo[2.2.2]octane (DABCO),1,5-diazabicyclo[4.3.0]nonene (DBN), and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

Lithium salts suitable for use in the P1a process include halide saltsand sulfonate salts, such as LiBr, LiCl, LiI, LiOTs, and LiOMs. A classof suitable lithium salts is the lithium halide salts, and a sub-classof suitable lithium halide salts is LiBr, LiCl, and LiI.

Alkoxide bases suitable for use in the P1a process include the alkalimetal alkoxides such as the C₁₋₄ alkoxides of lithium, sodium andpotassium. The alkoxide base can be, for example, LiOMe, NaOMe, NaOEt,KOMe, KOEt, t-BuONa, or t-BuOK.

Treating in Step A of the P1a process can suitably be conducted in anorganic solvent. The organic solvent can be an aprotic solvent, whereinthe aprotic solvent is suitably an ether, a tertiary amide, anN-alkylpyrrolidone, a sulfoxide, or an aromatic hydrocarbon. The solventcan be, for example, THF, MTBE, DME, dioxane, DMF, DMAC,N-methylpyrrolidone, N-ethylpyrrolidone, DMSO, or toluene. A class ofsuitable solvents is the ethers (e.g., THF).

The treating in Step A of the P1a process can be conducted at anytemperature at which the reaction forming Compound V can be detected.The treating can suitably be conducted at a temperature in a range offrom about −20 to about 60° C., is typically conducted at a temperaturein a range of from about 0 to about 30° C., and is more typicallyconducted at a temperature in a range of from about 15 to about 25° C.

The tertiary amine base (e.g., DABCO) or alkoxide base can be employedin Step A in any proportion with respect to Compound IX which results inthe formation of at least some of the desired compound of Formula V, butthe base is typically employed in a proportion which, under the reactionconditions (e.g., temperature) employed, can optimize conversion ofCompound IX to Compound V. The base is suitably employed in an amount ina range of at least about 0.1 equivalent (e.g., from about 0.1 to about5 equivalents) per equivalent of Compound IX, is typically employed inan amount in a range of from about 1 to about 5 equivalents perequivalent of Compound IX, and is more typically employed in an amountin a range of from about 2 to about 4 equivalents per equivalent ofCompound IX.

The lithium salt (e.g., LiBr) used in combination with the tertiaryamine base can be employed in Step A in any proportion with respect toCompound IX which results in the formation of at least some of thedesired compound of Formula V, but salt is typically employed in aproportion which, under the reaction conditions (e.g., temperature)employed, can optimize conversion of Compound IX to Compound V. The Lisalt is suitably employed in an amount in a range of at least about 0.1equivalent (e.g., from about 0.1 to about 5 equivalents) per equivalentof Compound IX, is typically employed in an amount in a range of fromabout 1 to about 5 equivalents per equivalent of Compound IX, and ismore typically employed in an amount in a range of from about 2 to about4 equivalents per equivalent of Compound IX.

The treatment time can vary widely depending upon, inter alia, the scaleof the treatment (e.g., laboratory bench v. pilot plant), the treatmenttemperature and the choice and relative amounts of reactants andreagents, but the reaction time is typically in a range of from about 15minutes to about 24 hours.

In one embodiment, Step A of Process P1a comprises adding the Li salt(e.g., LiBr) to Compound IX dissolved or suspended in an organic solvent(e.g., an ether such as THF), and then adding the tertiary amine base(e.g., DABCO) to form a reaction mixture, and then ageing the resultingmixture to obtain Compound V. The additions of Li salt and amine basecan be conducted with agitation (e.g., stirring). The reaction mixtureis aged at a suitable reaction temperature as set forth above andoptionally with agitation until the desired degree of conversion ofCompound IX is achieved or until conversion is complete. The addition ofthe Li salt and amine base to Compound IX can be done at the desiredreaction temperature which is then maintained during ageing, or theaddition of the Li salt and amine base can be done below the desiredreaction temperature and the mixture brought to the desired temperaturefor ageing. The ageing can be quenched by addition of an acid. Thedesired Compound V can be recovered by extraction with a suitableorganic solvent, followed by evaporative removal of the solvent.

The present invention also includes a process (alternatively referred toherein as “Process P2” or the “P2 process”) for preparing a compound ofFormula VIII:

which comprises reacting an alkylating agent of formula R⁵-Z with acompound of Formula VIII:

in a polar aprotic solvent and in the presence of a base selected from amagnesium base and a calcium base; wherein:bond

in the ring is a single bond or a double bond;W is —H or —C₁₋₆ alkyl;Z is halogen or —SO₃-Q wherein Q is (i) C₁₋₆ alkyl or (ii) phenyloptionally substituted with 1 or 2 substituents each of which isindependently a C₁₋₆ alkyl;R^(S) is —O—C₁₋₆ alkyl or N(R^(V))R^(W) wherein R^(V) and R^(W) are eachindependently —C₁₋₆ alkyl or R^(V) and R^(W) together with the N atom towhich they are both attached form a 4- to 6-membered saturatedheterocyclic ring optionally containing a heteroatom in addition to thenitrogen attached to R^(V) and R^(W) selected from N, O, and S, wherethe S is optionally oxidized to S(O) or S(O)₂, and wherein the saturatedheterocyclic ring is optionally substituted with 1 or 2 substituentseach of which is independently a C₁₋₆ alkyl group;R⁵ is:

-   -   (1) —C₁₋₆ alkyl,    -   (2) —C₃₋₈ cycloalkyl optionally substituted with from 1 to 4        substituents each of which is independently —C₁₋₆ alkyl or        —O—C₁₋₆ alkyl,    -   (3) —C₁₋₆ alkyl substituted with C₃₋₈ cycloalkyl, wherein the        cycloalkyl is optionally substituted with from 1 to 4        substituents each of which is independently —C₁₋₆ alkyl or        —O—C₁₋₆ alkyl,    -   (4) —C₁₋₆ alkyl substituted with aryl, wherein the aryl is        optionally substituted with from 1 to 5 substituents each of        which is independently —C₁₋₆ alkyl, —C₁₋₆ alkylene-O—C₁₋₆ alkyl,        or halogen, or    -   (5) —C₁₋₆ alkyl substituted with a 5- or 6-membered        heteroaromatic ring containing from 1 to 4 heteroatoms        independently selected from N, O and S, wherein the        heteroaromatic ring is optionally substituted with from 1 to 4        substituents each of which is independently —C₁₋₆ alkyl;        and R¹, R², and R³ are each independently as originally defined        above.

Compounds embraced by Formula VIII include compounds of the presentinvention (i.e., when W is H) and compounds which can be used asintermediates (i.e., when W is C₁₋₆ alkyl) in the preparation ofcompounds of the present invention. The use of a magnesium base or acalcium base (preferably a magnesium base) can favor the desiredN-alkylation over O-alkylation; e.g., the formation of a compound ofFormula VII over the formation of the following compound:

The base employed in Process P2 can be a magnesium-containing base or acalcium-containing base. Magnesium and calcium bases suitable for use inthe process include those of formula M(R^(x))₂, wherein M is Mg or Ca,and each R^(x) is independently H or —O—C₁₋₆ alkyl. Exemplary basesinclude MgH₂, Mg(OMe)₂, Mg(OH)₂, Mg(OEt)₂, MgHOMe, MgHOEt, CaH₂,Ca(OMe)₂ and Ca(OEt)₂. The base is preferably a magnesium base. In oneembodiment, the P2 process is as originally set forth above, wherein thebase comprises a magnesium base of formula Mg(R^(x))₂ where R^(x) is asdefined above. In an aspect of this embodiment, the base is aMg(O—C₁₋₄-alkyl)₂. In another aspect of this embodiment, the base isMg(OMe)₂.

The base can be employed in any proportion with respect to Compound VIIIand alkylating agent (e.g., alkyl halide) which results in the formationof at least some of the desired N-alkylated compound of Formula VII, butthe base is typically employed in a proportion which, under the reactionconditions (e.g., temperature) employed, can optimize conversion ofCompound VIII to Compound VII. The base is suitably employed in anamount in a range of from about 0.5 to about 10 equivalents perequivalent of Compound VIII, is typically employed in an amount in arange of from about 1 to about 10 equivalents per equivalent of CompoundVIII, and is more typically employed in an amount in a range of fromabout 1 to about 5 equivalents (e.g., from about 1.5 to about 2equivalents) per equivalent of Compound VIII.

The alkylating agent employed in Process P2 is of formula R⁵-Z, whereinR⁵ is as defined above and Z is halogen (i.e., F, Cl, Br, or I) or—SO₃-Q wherein Q is (i) C₁₋₆ alkyl or (ii) phenyl optionally substitutedwith 1 or 2 substituents each of which is independently a C₁₋₆ alkyl. Inone embodiment, the P2 process is as originally set forth above or asset forth in a preceding embodiment, wherein the alkylating agent is offormula R⁵-Z, wherein R⁵ is C₁₋₆ alkyl and Z is chloride, bromide,iodide, mesylate, or tosylate. In an aspect of this embodiment, Z isiodide or tosylate. In another aspect of this embodiment, the alkylatingagent is MeI or methyl tosylate, and in a feature of this aspect thealkylating agent is methyl tosylate.

The alkylating agent can be employed in any proportion with respect tothe base and Compound VIII which results in the formation of at leastsome of the desired N-alkylated compound of Formula VII, but thealkylating agent is typically employed in a proportion which, under thereaction conditions (e.g., temperature) employed will optimizeconversion of Compound VIII to Compound VII. The alkylating agent issuitably employed in an amount in a range of from about 0.5 to about 20equivalents per equivalent of Compound VIII, and is typically employedin an amount in a range of from about 1 to about 20 equivalents perequivalent of Compound VIII. The alkylating agent (e.g., alkyl halide)is more typically employed in an amount in a range of from about 1 toabout 10 equivalents (e.g., from about 1 to 5 equivalents) perequivalent of Compound VIII. The alkylating agent is preferably employedin excess with respect to Compound VIII, such as in an amount in a rangeof from about 2 to about 6 equivalents (e.g., from about 3 to about 5equivalents, or about 4 equivalents) per equivalent of Compound VIII.

The solvent employed in Process P2 can be any polar aprotic solventwhich under the conditions employed is in the liquid phase, ischemically inert, and will dissolve, suspend, and/or disperse thereactants so as to bring them into contact and permit the formation ofthe desired Compound VII. The solvent is preferably one which under theconditions employed in the process favors N-alkylation to the desiredCompound VII over O-alkylation to an O-alkylated by-product. The polaraprotic solvent is suitably a halogenated alkane, an ether, an ester, atertiary amide, an N-alkylpyrrolidone, a sulfoxide, or a nitrile; and istypically a tertiary amide, an N-alkylpyrrolidone, or a sulfoxide. Inone embodiment, the P2 process is as originally set forth above or asset forth in a preceding embodiment, wherein the polar aprotic solventcomprises a N,N-di-(C₁₋₆ alkyl)-C₁₋₆ alkylamide, a N—(C₁₋₆alkyl)pyrrolidone, or a di-(C₁₋₆ alkyl)sulfoxide. In an aspect of thisembodiment, the polar aprotic solvent comprises a N,N-di-(C₁₋₃alkyl)-C₁₋₃ alkylamide, a N—(C₁₋₃ alkyl)pyrrolidone, or a di-(C₁₋₃alkyl)sulfoxide. In another aspect of this embodiment, the polar aproticsolvent is DMF, DMAC, N-methylpyrrolidone, N-ethylpyrrolidone, or DMSO.In a feature of this aspect, the polar aprotic solvent is DMF.

Process P2 can be conducted at any temperature at which the reaction(N-alkylation) forming Compound VII can be detected. The reaction cansuitably be conducted at a temperature in a range of from about −20 toabout 100° C., is typically conducted at a temperature in a range offrom about 0 to about 100° C., and is more typically conducted at atemperature in a range of from about 15 to about 80° C. In oneembodiment of the P2 process the temperature is in a range of from about20 to about 60° C., wherein the process step is initially conducted atabout 20° C. and subsequently heated to a temperature of about 60° C.

An embodiment of the P2 process is the process for preparing a compoundof Formula VII-A:

which comprises reacting an alkylating agent of formula R⁵-Z with acompound of Formula VIII-A:

in a polar aprotic solvent and in the presence of a magnesium base;wherein:W is —H or —C₁₋₆ alkyl;X¹ and X² are each independently:

(1) —H,

(2) —C₁₋₄ alkyl,

(3) —C₁₋₄ haloalkyl,

(4) —O—C₁₋₄ alkyl,

(5) halogen,

(6) —CN,

(7) —C(═O)NH₂,

(8) —C(═O)NH(—C₁₋₄ alkyl),

(9) —C(═O)N(—C₁₋₄ alkyl)₂, or

(10) —SO₂—C₁₋₄ alkyl;

Z is —Cl, —Br, —I, or tosylate;

R^(S) is —O—C₁₋₆ alkyl or N(R^(V))R^(W) wherein R^(V) and R^(W) are eachindependently —C₁₋₆ alkyl; and

R⁵ is —C₁₋₆ alkyl.

Additional embodiments of the P2 process include the process as justdescribed in the preceding embodiment incorporating one or more of thefeatures (i) to (vi) as follows:

(i) the magnesium base comprises MgH₂ or Mg(O—C₁₋₃ alkyl)₂ (or isMg(OMe)₂);

(ii) the polar aprotic solvent is a N,N-di-(C₁₋₃ alkyl)-C₁₋₃ alkylamide,a N—(C₁₋₃ alkyl)pyrrolidone, or a di-(C₁₋₃ alkyl)sulfoxide (e.g., thesolvent is DMF, DMAC, N-methylpyrrolidone, N-ethylpyrrolidone, or DMSO;or the solvent is DMF);

(iii) the reaction is conducted at a temperature in a range of fromabout 0 to about 100° C. (or from about 20 to about 60° C.);

(iv) the alkylating agent R⁵-Z is a C₁₋₄ alkyl iodide or a C₁₋₄ alkyltosylate (or is MeI or methyl tosylate);

(v) the alkylating agent R⁵-Z is employed in an amount in a range offrom about 1 to about 5 equivalents (or from about 3 to about 5equivalents) per equivalent of Compound VIII-A; and

(vi) the magnesium base is employed in an amount in a range of fromabout 1 to about 5 equivalents (or from about 1.5 to about 2equivalents) per equivalent of Compound VIII-A).

Another embodiment of Process P2 is the process as originally set forthabove or as described in a preceding embodiment, which further comprisesrecovering Compound VII from the reaction medium. Process P2 can resultin the formation of O-alkylated by-product, which can be separated fromthe desired N-alkylated product (i.e., Compound VII) by methods known inthe art such as washing the precipitated solids with suitable solventsor via chromatography.

The present invention also includes a process (alternatively referred toherein as “Process P3” or the “P3 process”) for preparing a compound ofFormula IV as defined above, which comprises treating a compound ofFormula X:

with (i) a tertiary amine base in the presence of a lithium salt or (ii)an alkoxide base, to obtain a compound of Formula IV, wherein bonds

and

and R^(T)* are each as defined above in the P1a process; and all of thevariables in Formula X are as originally defined above in the P1process. An embodiment of the P3 process is the process as just defined,wherein the compound of Formula X is a compound of Formula X-A:

the compound of Formula IV is a compound of Formula IV-A; and R⁵, X¹ andX² are each as defined in Compound IV-A above. The description of thechoice and amounts of base (i.e., tertiary amine base or alkoxide base)and lithium salt, the treatment temperature, the treatment time, thechoice and use of organic solvents, methods of quenching and recovery,etc. set forth above for Step A of Process P1a applies to Process P3 aswell and is considered part of the description of Process P3.

Process P2 is an alkylation process in which the R⁵ substituent is addedto the ring nitrogen to provide the desired N-alkylated compound.Process P3, on the other hand, is a process in which cyclization of thering affords the desired N-alkylated compound, the R⁵ substituent havingbeen attached to the N atom prior to ring closure. (The R⁵ group can,for example, be introduced onto the N atom prior to cyclization byreductive amination with the appropriate aldehyde or ketone in thepresence of a reducing agent such as a borohydride—see, e.g., Step 2 ofExample 92.) When R⁵ is a bulky group (e.g., a branched alkyl group suchas isopropyl or isobutyl), alkylation of the ring N can be stericallyhindered resulting in relatively low yields of the desired compound VIIin Process P2. In such cases (and where R^(S) is N(R^(V))R^(W)), ProcessP3 can be preferred, because the cyclization is comparatively unaffectedby the size of the R⁵ group and because methods for introducing R⁵ intothe uncyclized precursor (e.g., reductive amination) can be moreefficient relative to the post-cyclization alkylation of the P2 process.

It is understood that tautomers can exist for Compound IV in Process P1and P3, Compound V in Process P1, and Compound VII and Compound VIII inProcess P2 as a result of keto-enol tautomerism. The P1 and P2 and P3processes encompass all tautomeric forms, individually and in mixtures.

The progress of any reaction step of any chemical process set forthherein, including processes P1 and P2 and P3, can be followed bymonitoring the disappearance of a reactant (e.g., Compound VIII) and/orthe appearance of the desired product (e.g., Compound VII) using suchanalytical techniques as TLC, HPLC, IR, NMR or GC.

Unless a contrary meaning is clear from the context, a reference hereinto “equivalent” or “equivalents” means molar equivalent(s).

The following examples serve only to illustrate the invention and itspractice. The examples are not to be construed as limitations on thescope or spirit of the invention. In the following examples “MS (M+1)”refers to the mass of the molecular ion plus 1 of the subject compoundas determined by mass spectroscopy.

EXAMPLE 1 Methyl6-(4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate

Step 1: 1-(4-Fluorobenzyl)piperidine-2-one

To a suspension of sodium hydride (2.4 g, 0.1 mol) in anhydrous THF (400mL) was added piperidine-2-one (9.0 g, 90 mmol) in anhydrous THF (20 mL)over 10 minutes. After 20 minutes, the resultant thick slurry wastreated with 4-fluorobenzyl bromide (18.9 g, 99.9 mmol). The reactionmixture was refluxed overnight. The resultant mixture was cooled to 0°C. and treated with H₂O (10 mL) cautiously. The mixture was stirred for10 minutes and concentrated under vacuum. The residue was partitionedbetween ethyl acetate (300 mL) and H₂O. The organic extract was washedwith brine, dried with MgSO₄, filtered, and concentrated under vacuum.The residual oil was subjected to column chromatography on silica geleluting with 50%-70% ethyl acetate in hexanes. The appropriate fractionswere combined and concentrated to afford the benzylated piperidinone asa white solid.

¹HNMR (400 MHz, CDCl₃) δ 7.23 (dd, J=8.7 Hz, 5.4 Hz, 2H), 7.00 (t, J=8.7Hz, 2H), 4.56 (s, 2H), 3.18 (t, J=6 Hz, 2H), 2.46 (t, J=6 Hz, 2H), 1.79(m, 4H).

Step 2: 1-(4-Fluorobenzyl)-3-(phenylsulfinyl)piperidin-2-one

To a cooled (0° C.) solution of 1-(4-fluorobenzyl)piperidine (5.0 g,24.1 mmol) in anhydrous THF (100 mL) was added lithiumbis(trimethylsilyl)amide (1.0 M in THF, 53 mL, 53 mmol) dropwise, andthe solution was stirred for one half hour. The solution was treatedwith methyl benzene sulfinate (5.65 g, 36.1 mmol) in anhydrous THF (3mL) dropwise. After 30 minutes at 0° C., the resultant mixture wasquenched with water and partitioned between 10% KHSO₄ and CHCl₃, thelayers separated and the aqueous extracted several more times withCHCl₃. The organic extract was dried with Na₂SO₄, filtered, andconcentrated under vacuum to afford1-(4-fluorobenzyl)-3-(phenylsulfinyl)piperidin-2-one as a waxy solidthat was taken on to the next step. ES MS M+1=332

Step 3: 1-(4-Fluorobenzyl)-5,6-dihydropyridin-2-(1H)-one

To a solution of 1-(4-fluorobenzyl)-3-(phenylsulfinyl)piperidin-2-one(0.37 g, 1.11 mmol) in toluene (15 mL) was added solid Na₂CO₃ (2 g, 18.8mmol). The reaction mixture was refluxed for about 6 hours. Theresultant solution was filtered and concentrated under vacuum and theresidue chromatographed on silica eluting with a gradient of 040%EtOAc/Hexanes to give the product as colorless glass.

¹HNMR (400 MHz, CDCl₃) δ 7.26 (m, 2H), 7.01 (m, 2H), 6.56 (dt, J=9.9 Hz,4.2 Hz, 1H), 6.00 (dt, J=9.7 Hz, 1.8 Hz, 1H), 4.59 (s, 2H), 3.32 (t,J=7.2 Hz, 2H), 2.33 (m, 2H).

Step 4: Methyl[(2-methoxy-2-oxoethyl)amino] (oxo)acetate

To a cooled (0° C.) solution of the glycine methyl ester HCl salt (30.0g, 0.24 mol) in methylene chloride (500 mL) was added triethylamine(50.8 g, 0.50 mol). Methyl oxalyl chloride (29.3 g, 0.24 mol) wascarefully added dropwise. The reaction solution warmed to roomtemperature and stirred overnight. The product mixture was partitionedbetween H₂O and methylene chloride. The organic extract was dried withNa₂SO₄ and concentrated under vacuum to afford the title compound as abrown oil.

¹HNMR (400 MHz, CDCl₃) δ 7.59 (br, 1H), 4.14 (d, J=5.6 Hz, 2H), 3.93 (s,3H), 3.79 (s, 3H). ES MS M+1=176

Step 5: Methyl 5-methoxy-1,3-oxazole-2-carboxylate

To a warm (35-40° C.) suspension of phosphorous pentoxide (77.7 g, 109mmol) in anhydrous acetonitrile (200 mL) was addedmethyl[(2-methoxy-2-oxoethyl)amino](oxo)acetate (19.19 g, 109.6 mmol).The reaction mixture was heated to 65° C., then stirred overnight atroom temperature. The product mixture was cooled to 0° C. and carefullyquenched with ice and brine keeping the reaction from generating anunsuitable exotherm. The resultant mixture was extracted with ethylacetate (600 mL). The organic extract was washed with brine, dried withNa₂SO₄, then concentrated under vacuum. The residue was subjected tocolumn chromatography on silica gel eluting with 100% CH₂Cl₂. Theappropriate fractions were combined and concentrated to afford the titlecompound as a light yellow solid that was used without furtherpurification.

¹H NMR (400 MHz, CDCl₃) δ 6.36 (s, 1H), 4.01 (s, 3H), 3.96 (s, 3H). ESMS M+1=158

Step 6: Methyl6-(4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate

In a sealed tube, 1-(4-fluorobenzyl)-5,6-dihydropyridin-2-(1H)-one (3.84g, 18.7 mmol), and methyl 5-methoxy-1,3-oxazole-2-carboxylate preparedin Step 5 (2.94 g, 18.7 mmol), were combined. The reaction mixture washeated at 120° C. After 24 hours, the resultant mixture was cooled andmethanol saturated with HCl (2 mL) was added. The product mixturestirred at room temperature for 40 minutes, then was concentrated undervacuum. The residual crude material was diluted with DMSO (6.0 mL) andfiltered to give the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ 12.96 (br, 1H), 8.39 (s, 1H), 7.31 (m, 2H),7.06 (t, J=8.5 Hz, 2H), 4.72 (s, 2H), 3.94 (s, 3H), 3.50 (m, 4H). ES MSM+1=331

Step 7: Methyl6-(4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate2-oxide

To a solution of methyl6-(4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate(0.509 g, 1.541 mmol) in acetic acid (2 mL) was added hydrogen peroxide(35% wt % in H₂O, 0.262 g, 7.705 mmol). The reaction mixture was heatedto 100° C. for 1 hour. The product mixture was concentrated under vacuumand purified by reverse phase HPLC eluting with 5%-95% acetonitrile(0.1% TFA) in H₂O (0.1% TFA) to afford the title compound as a yellowsolid.

¹HNMR (400 MHz, CD₃OD) δ 7.95 (s, 1H), 7.38 (dd, J=5.3 Hz, 8.6 Hz, 2H),7.08 (t, J=8.8 Hz, 2H), 4.71 (s, 2H), 3.93 (s, 3H), 3.56 (t, J=6.7 Hz,2H), 2.89 (t, J=6.7 Hz, 2H). ES MS M+1=347

Step 8: Methyl6-(4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate

To methyl6-(4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate2-oxide (0.178 g, 0.514 mmol) was added acetic anhydride (0.157 g, 1.542mmol) and refluxed. After 1 hour, the reaction mixture was concentratedunder vacuum, then sodium methoxide (30 wt. % in methanol, 0.083 g,1.540 mmol) was added. After stirring at room temperature for 1 hour,the product mixture was concentrated under vacuum. The residue waspurified by reverse phase HPLC eluting with 5%-95% acetonitrile (0.1%TFA) in H₂O (0.1% TFA) to afford the title compound as a pale yellowsolid.

¹HNMR (400 MHz, CDCl₃) δ 7.30 (dd, J=5.3 Hz, 8.4 Hz, 2h), 7.06 (t, J=8.5Hz, 2H), 4.71 (s, 2H), 3.93 (s, 3H), 3.46 (t, J=6.5 Hz, 2H), 3.32 (t,J=6.5 Hz, 2H).

ES MS M+1=347

EXAMPLE 26-(4-Fluorobenzyl)-4-hydroxy-N,N-dimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

To a cooled (−10° C.) solution of dimethylamine (2M in THF, 0.002 g,0.035 mmol) was slowly added trimethylaluminum (2M in toluene, 0.002 g,0.035 mmol) and stirred for 30 minutes at room temperature. The reactionmixture was cooled to −10° C. and methyl6-(4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate(0.004 g, 0.012 mmol, Example 1, Step 8) in THF (5 mL) was added. Thereaction stirred at room temperature for 2 hours, then transferred viasyringe to a solution of 1:1 CH₂Cl₂:0.5 N aq. HCl at 0° C. and stirredfor 1 hour. The product mixture was separated, and the aqueous wasextracted three times with CH₂Cl₂. The aqueous layer was treated withsaturated Na₂CO₃ solution to pH 5 and extracted three times with CH₂Cl₂again. The organic combined extracts were dried with Na₂SO₄ andconcentrated under vacuum. The residue was purified by reverse phaseHPLC eluting with 5%-95% acetonitrile (0.1% TFA) in H₂O (0.1% TFA) toafford the title compound as a light yellow solid.

¹H NMR (400 MHz, CD₃OD) δ 7.39 (dd, J=5.3 Hz, 8.6 Hz, 2H), 7.09 (t,J=8.8 Hz, 2H), 4.74 (s, 2H), 3.50 (t, J=6.4 Hz, 2H), 3.05 (s, 3H), 2.96(s, 3H), 2.67 (t, J=6.4 Hz, 2H) ppm. ES MS M+1=360

EXAMPLES 3-6

The compounds in the following table were prepared in accordance withthe procedure set forth in Example 2 using the appropriate analogousstarting materials. Example Compound Data 3

¹HNMR (400 MHz, CD₃OD) δ 7.39 (dd, J=5.6 Hz, 8.7 Hz, 2H), 7.09 (t, J=8.7Hz, 2H), 4.74 (s, 2H), 4.39 (p, J=7.9 Hz, 1H), 3.49 (t, J=6.1 Hz, 2H),3.06 (t, J=6.1 Hz, 2H), 2.32 (m, 2H), 2.04 (m, 2H), 1.78 (m, 2H) ppm. ESMS M + 1 = 386 4

¹HNMR (400 MHz, CDCl₃) δ 13.53 (br, 1H), 7.63 (br, 1H), 7.30 (dd, J=5.6Hz, 8.5 Hz, 2H), 7.06 (t, J=8.5 Hz, 2H), 4.71 (s, 2H), 3.51 (m, 2H),3.46 (m, 2H), 2.86 (m, 1H), 1.88 (br, 1H), 0.83 (q, J=5.9 Hz, 2H), 0.71(m, 2H) ppm. ES MS M + 1 = 372 5

¹HNMR (400 MHz, CDCl₃) δ 7.30 (dd, J=5.7 Hz, 8.8 Hz, 2H), 7.06 (t, J=8.8Hz, 2H), 6.89 (d, J=7.3 Hz, 1H), 4.82 (br, 1H), 4.71 (s, 2H), 4.17 (m,1H), 3.47 (t, J=6.3 Hz, 2H), 3.35 (t, J=6.3 Hz, 2H), 1.26 (d, J=6.1 Hz,6H) ppm. ES MS M + 1 = 374 6

¹H NMR (400 MHz, CD₃OD) δ 7.38 (m, 2H), 7.08 (m, 2H), 4.73 (s, 2H), 3.48(t, J=6.6 Hz, 2H), 3.08 (t, J=6.5 Hz, 2H), 2.85 (s, 3H) ppm. MS m/z346.3 (M + 1).

EXAMPLE 76-(4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylicacid

To methyl6-(4-fluorobenzyl)-4-hydroxy-3,5-dioxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate(0.178 g, 0.514 mmol) in wet methanol was added N,N-dimethylamine inMeOH (4.0 eq.). The reaction mixture was put in a microwave reactorwhere it was heated at 130° C. for 1.5 hours, after which the reactionmixture was concentrated under vacuum. The residue was purified byreverse phase HPLC eluting with 5%-95% acetonitrile (0.1% TFA) in H₂O(0.1% TFA) to afford the title compound as a solid. Alternatively, thestarting material can be treated with LiOH in 1:1:1 THF/MeOH/H₂O to givethe product.

¹HNMR (400 MHz, CD₃OD) δ 7.38 (m, 2H), 7.06 (m, 2H), 4.74 (s, 2H), 3.48(m, 2H), 3.32 (m, 2H). ES MS M+1=333

EXAMPLE 8N-[6-(4-fluorobenzyl)-3,4-dihydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl]-N-methylmethanesulfonamide

Step 1: 1-(glycyloxy)butane chloride

To a suspension of glycine hydrochloride (10 g, 89.6 mmol) in 250 mLbutanol under nitrogen was added thionyl chloride (45.7 mL, 627 mmol)dropwise. After the addition was complete, the solution was heated at70° C. overnight. The volatile components were removed on theroto-evaporator and the residue was suspended and evaporated fromtoluene three times. The resulting crude gum was dissolved in an equalweight of toluene for easy transfer and was used as is in the nextreaction.

¹H NMR (400 MHz, CDCl₃) δ 8.5 (bs, 3H), 4.18 (t, J=6.7 Hz, 2H), 4.0 (bs,2H), 1.62 (m, 2H), 1.38 (m, 2H), 0.92 (t, J=7.4 Hz, 3H) ppm. ES MSM+1=132.

Step 2: Butyl N-[ethoxy(oxo)acetyl]glycinate

A 1:1 by weight solution of 1-(glycyloxy)butane chloride

(10 g, 59.6 mmol) in toluene (10 g) was treated with EtOH (100 mL), thenTriethylamine (10 mL, 71.6 mmol) and diethyloxalate (16.2 mL, 119.3mmol) and heated to 50° C. for three hours. The volatile components wereremoved on the roto-evaporator and the residue was dissolved in CHCl₃,washed two times with 10% KHSO₄, the aqueous layer was washed two timeswith CHCl₃, the organic layers were combined, dried over Na₂SO₄,filtered and evaporated to give the crude oil, which was chromatographedon silica eluting first with 20% EtOAc/hexanes and then with 50%EtOAc/hexanes to give clean product.

¹H NMR (400 MHz, CDCl₃) δ 7.56 (bs, 1H), 4.37 (q, J=7.2 Hz, 2H), 4.2 (t,J=6.6 Hz, 2H), 4.12 (d, J=5.5 Hz, 2H), 1.64 (p, J=6.8 Hz, 2H), 1.39 (t,J=7.15 Hz, 3H), 1.37 (m, buried, 2H), 0.94 (t, J=7.4 Hz, 3H) ppm. ES MSM+1=232

Step 3: Ethyl 5-butoxy-1,3-oxazole-2-carboxylate

A suspension of P₂O₅ (22 g, 155.6 mmol) in CH₃CN (50 mL) under nitrogenwas warmed to 50° C. and treated with butylN-[ethoxy(oxo)acetyl]glycinate (6 g, 25.9 mmol) dissolved in 10 mLCH₃CN. The mixture was heated to 65° C. for 1.5 hours, then cooled in anice bath. Ice and brine were added to the reaction mixture, then EtOAcwas added and the mixture transferred to a separatory funnel. CHCl₃ wasadded to dissolve solids and the organic layer was isolated. The aqueouslayer was washed repeatedly with CHCl₃ and EtOAc, the organic layerswere combined and dried with Na₂SO₄, then concentrated. The residue waschromatographed on silica eluting with a gradient of 0-30% EtOAc/Hexanesto give the product as a clear, colorless oil.

¹H NMR (400 MHz, CDCl₃) δ 6.33 (s, 1H), 4.42 (q, J=7.15 Hz, 2H), 4.18(t, J=6.4 Hz, 2H), 1.8 (p, J=6.4 Hz, 2H), 1.47 (p, J=7.4 Hz, 2H), 1.41(t, J=7.15 Hz, 3H), 0.97 (t, J=7.4 Hz, 3H) ppm. ES MS M+1=214.

Step 4: Ethyl6-(4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate

In a heavy walled round bottom flask with screw top were combined ethyl5-butoxy-1,3-oxazole-2-carboxylate (2.53 g, 11.88 mmol) and1-(4-fluorobenzyl)-5,6-dihydropyridin-2-(1H)-one (1.22 g, 5.94 mmol; seeExample 1, Step 3) and trifluoroacetic acid (0.46 mL, 5.94 mmol). Thevessel was sealed and placed in an oil bath heated to 130° C. Thereaction mixture was stirred for 3 days. The dark brown reaction mixturewas cooled and a crystalline precipitate formed. The mixture was dilutedwith ether and the solids collected by filtration and washed with etherto give the product as tan shiny plates. Further product can be obtainedby evaporating the mother liquor, adding more trifluoroacetic acid andre-heating the mixture.

¹H NMR (400 MHz, CDCl₃) δ 12.9 (s, 1H), 8.42 (s, 1H), 7.31 (dd, J=5.3,8.8 Hz, 2H), 7.06 (t, J=8.6 Hz, 2H), 4.72 (s, 2H), 4.41 (q, J=7.15 Hz,2H), 3.50 (m, 4H), 1.41 (t, J=7.15 Hz, 3H) ppm. ES MS M+1=345.

Step 5: Ethyl6-(4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate

To a solution of chloroform (10 mL) and methanol (10 mL) was addedtrimethylsilyl diazomethane (2.0 M in hexanes, 5 mL, 0.01 mole). Afterstirring for 10 minutes at room temperature, ethyl6-(4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate(1.6 g, 3.5 mmol) in chloroform was added. After 7 hours, methanol (5mL) and trimethylsilyl diazomethane (2.5 mL, 0.005 mole) was added tothe reaction mixture. After 1 hour, glacial acetic acid (3 mL) was addedwith gas evolution observed. The solution was stirred for 0.5 hour. Theproduct mixture was concentrated under vacuum. The residual material wassubjected to column chromatography on silica gel eluting with 0-100%ethyl acetate in hexanes. The appropriate fractions were combined andconcentrated to afford the title compound as a foam.

¹H NMR (400 MHz, CDCl₃) δ 8.47 (s, 1H), 7.32 (dd, J=5.3, 8.5 Hz, 2H),7.03 (t, J=8.6 Hz, 2H), 4.73 (s, 2H), 4.45 (q, J=7.14 Hz, 2H), 4.11 (s,3H), 3.43 (t, J=6 Hz, 2H), 3.29 (t, J=6 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H)ppm. ES MS M+1=359

Step 6:6-(4-Fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylicacid

To a solution of ethyl6-(4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate(1.21 g, 3.38 mmol) in methanol (5 mL) and water (5 mL) and THF (5 mL)was added lithium hydroxide (0.425 g, 10.13 mmol). After 5 minutes, 1NHCl (3 equiv.) was added to the product mixture, which was then driedunder vacuum to provide the crude title compound.

¹H NMR (400 MHz, CDCl₃) δ 11.29 (br, 1H), 8.35 (s, 1H), 7.27 (m, 2H),7.03 (m, 2H), 4.73 (s, 2H), 4.15 (s, 3H), 3.55 (m, 4H) ppm. ES MSM+1=331

Step 7:6-(4-Fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carbonylchloride

A solution of6-(4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylicacid (1.11 g, 3.36 mmol) in thionyl chloride (0.4 g, 3.36 mmol) washeated to 110° C. After 0.5 hours, the product mixture was concentratedunder vacuum. The residue was suspended in toluene, evaporated, thensuspended in chloroform and evaporated to give the title compound. Theproduct was assayed by quenching in methanol solution to produce themethyl ester. ES MS M+1=345 (methyl ester forms after quench inmethanol)

Step 8:5-Amino-2-(4-fluorobenzyl)-8-methoxy-3,4-dihydro-2,6-naphthyridin-1(2H)-one

To a solution of sodium azide (0.24 g, 3.69 mmol) in water (2.5 mL) wasadded6-(4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carbonylchloride (1.17 g, 3.36 mmol) in acetone (15 mL). After 20 minutes, theproduct mixture was concentrated under vacuum to provide6-(4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carbonylazide. The crude azide (1.19 g, 3.35 mmol) in DMF (20 mL) was heated to110° C. After 20 minutes, the product mixture was cooled for 10 minutes,then 1N NaOH (3.3 mL) was added. After 20 minutes, the mixture wasconcentrated under vacuum, re-dissolved in toluene and CHCl₃ andevaporated. The residue was partitioned between CHCl₃ and saturatedsodium bicarbonate. The organic extract was dried with Na₂SO₄, filtered,and concentrated under vacuum to provide the title compound.

¹H NMR (400 MHz, CDCl₃) δ 7.88 (s, 1H), 7.32 (m, 2H), 7.03 (t, J=9 Hz,2H), 4.71 (s, 2H), 4.17 (s, 2H), 3.94 (s, 3H), 3.47 (t, J=6 Hz, 2H),2.58 (t, J=6 Hz, 2H) ppm. ES MS (M+1)=302.

Step 9:N-[6-(4-Fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl]methanesulfonamide

To a solution of5-amino-2-(4-fluorobenzyl)-8-methoxy-3,4-dihydro-2,6-naphthyridin-1(2H)-one(0.889 g, 2.95 mmol) in pyridine (5 mL) was added dropwisemethanesulfonyl chloride (0.575 g, 5.016 mmol). After stirring for anhour at room temperature, the product mixture was quenched with pH 7buffer, then concentrated under vacuum. The residue was dissolved inCHCl₃ and pH 7 buffer, the pH of the aqueous layer was adjusted to pH 5with 1N NaOH and the layers separated. Several more extractions withCHCl₃ were performed. The organic extracts were dried with Na₂SO₄,filtered, and concentrated under vacuum, then dissolved in toluene andCHCl₃ and evaporated to provide the title compound.

¹H NMR (400 MHz, CDCl₃) δ 7.33 (m, 2H), 7.04 (t, J=9 Hz, 2H), 4.70 (s,2H), 4.03 (s, 3H), 3.44 (t, J=6.5 Hz, 2H), 3.21 (s, 3H), 2.89 (t, J=6.4Hz, 2H) ppm. ES MS (M+1)=380.

Step 10:N-[6-(4-Fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl]-N-methylmethanesulfonamide

To a solution ofN-[6-(4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl]methanesulfonamide(0.097 g, 0.256 mmol) in DMF (2 mL) was added Cs₂CO₃ (0.083 g, 0.256mmol) and MeI (0.04 g, 0.28 mmol, dissolved in DMF). After stirring for2 hours, additional MeI (0.02 g, 0.14 mmol) was added. The productmixture was concentrated. The residue was partitioned between CHCl₃ andpH 7 buffer. The organic extract was dried with Na₂SO₄, filtered, andconcentrated under vacuum to provide the title compound.

¹H NMR (400 MHz, CDCl₃) δ 8.20 (s, 1H), 7.26 (m, 2H), 7.04 (t, J=9 Hz,2H), 4.70 (s, 2H), 4.06 (s, 3H), 3.43 (t, J=7 Hz, 2H), 3.21 (s, 3H),3.03 (m, 5H) ppm. ES MS (M+1)=394.

Step 11:N-[6-(4-Fluorobenzyl)-4-methoxy-2-oxido-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl]-N-methylmethanesulfonamide

To a solution ofN-[6-(4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl]-N-methylmethanesulfonamide(0.35 g, 0.89 mmol) in CH₂Cl₂ (10 mL) was added mCPBA (1.08 g, 6.23mmol) in portions. After stirring for 3.5 hours at reflux, the productmixture was cooled to room temperature, 1 mL of ethanol was added, andthe solution was concentrated. The residue was partitioned between CHCl₃and saturated Na₂SO₃. The organic layer was extracted repeatedly withsaturated sodium bicarbonate. The organic extract was dried with Na₂SO₄,filtered, and concentrated under vacuum to provide the crude titlecompound.

¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.30(m, 2H), 7.03 (t, J=7 Hz,2H), 4.72 (d, J=14.6 Hz, 1H), 4.65 (d, J=14.6 Hz, 1H), 4.01 (s, 3H),3.45 (m, 2H), 3.29 (s, 3H), 3.20 (s, 3H), 3.18 (m, 1H), 2.87 (m, 1H)ppm. ES MS (M+1)=410.

Step 12:N-[6-(4-Fluorobenzyl)-3-hydroxy-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl]-N-methylmethanesulfonamide

A solution ofN-[6-(4-fluorobenzyl)-4-methoxy-2-oxido-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl]-N-methylmethanesulfonamide(0.36 g, 0.889 mmol) in acetic anhydride (10 mL) was heated to 110° C.for 3 hours, then evaporated to dryness to give the intermediate6-(4-fluorobenzyl)-4-methoxy-1-[methyl(methylsulfonyl)amino]-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridin-3-ylacetate (ES MS (M+1)=452). The crude material was dissolved in methanol(6 mL) and treated with sodium methoxide (30% by weight in methanol, 0.5mL, 2.6 mmol). After 1 hour, the product mixture was neutralized with 6N HCl, then concentrated. The residue was partitioned between CHCl₃ and10% KHSO₄. The organic extract was dried with Na₂SO₄, filtered, andconcentrated under vacuum to provide the title compound.

¹H NMR (400 MHz, CDCl₃) δ 7.29 (m, 2H), 7.03 (t, J=9 Hz, 2H), 4.71 (bs,2H), 4.06 (s, 3H), 3.41 (t, J=6 Hz, 2H), 3.28 (s, 3H), 3.11 (s, 3H), 2.8(m, 2H) ppm. ES MS (M+1)=410.

Step 13:N-[6-(4-fluorobenzyl)-3,4-dihydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl]-N-methylmethanesulfonamide

To a solution ofN-[6-(4-fluorobenzyl)-3-hydroxy-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl]-N-methylmethanesulfonamide(0.0207 g, 0.506 mmol) in CH₂Cl₂ (6 mL) was added 30% by weight HBr inpropionic acid (0.196 g HBr, 2.42 mmol). Alternatively, 30% HBr inacetic acid can be used. After 1.5 hours, the product mixture wasevaporated and the residue partitioned between CHCl₃ and 10% KHSO₄. Theorganic extract was dried with Na₂SO₄, filtered, and concentrated undervacuum. The residual material was purified using reverse phase HPLCeluting with 5%-95% acetonitrile (0.1% TFA) in H₂O (0.1% TFA) to affordthe title compound.

¹H NMR (400 MHz, CDCl₃) δ 12.97 (br, 1H), 7.28 (m, 2H), 7.04 (t, J=9 Hz,2H), 4.69 (s, 2H), 3.46 (t, J=7 Hz, 2H), 3.24 (s, 3H), 3.09 (s, 3H),2.98 (m, 2H) ppm. ES MS (M+1)=396.

EXAMPLE 9N-[6-(4-fluorobenzyl)-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]-N-methylacetamide

Step 1: Ethyl6-(4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate2-oxide

To ethyl6-(4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate(0.5 gm, 1.09 mmol; see Example 8, Step 4) in glacial acetic acid (25mL) at room temperature under nitrogen was added, with stirring, aqueousperoxide (30% by wt) (1.24 mL, 10.9 mmol). The reaction was warmed to100° C. and stirred for 1.5 hours. The reaction was allowed to cool,ethanol (1 mL) was added and volatile components were removed underreduced pressure. The resulting oil was placed under high vacuum for 16hours, then used as is. Alternatively, after cooling, water can be addedand the volatile components removed under reduced pressure. The residuecan be partitioned between CHCl₃ and saturated Na₂SO₃. The organicextract can be dried with Na₂SO₄, filtered, and concentrated undervacuum to provide the title compound.

¹H NMR (400 MHz, CDCl₃) δ 12.8 (br, 1H), 7.90 (s, 1H), 7.28 (dd, J=5.3,8.5 Hz, 2H), 7.04 (t, J=8.6 Hz, 2H), 4.69 (s, 2H), 4.43 (q, J=7.14 Hz,2H), 3.50 (t, J=6.8 Hz, 2H), 2.87 (t, J=6.8 Hz, 2H), 1.37 (t, J=7.14 Hz,3H) ppm. ES MS (M+1)=361.

Step 2: Sodium1-(ethoxycarbonyl)-6-(4-fluorobenzyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-4-olate

To ethyl6-(4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate2-oxide (2.3 gm, 6.38 mmol) in neat acetic anhydride (24 mL) was stirredunder nitrogen at 100° C. for 1 hour. The reaction was concentrated toan oil under reduced pressure and dry methanol (20 mL) was addedfollowed by a methanolic sodium methoxide solution (30% by wt) (4.54 mL,25.2 mmol). The reaction was stirred at room temperature for 1 hour. Thereaction was then concentrated to an oil under reduced pressure andcrystallized from a small amount of methanol (˜5 mL). The crystals werecollected by filtration, washed an additional 10 mL of methanol anddried in vacuo to give the desired product.

¹H NMR (400 MHz, CDCl₃) δ 9.49 (br, 1H), 7.30 (m, 2H), 7.06 (t, J=9 Hz,2H), 4.71 (s, 2H), 4.36 (q, J=7 Hz, 2H), 3.44 (t, J=6 Hz, 2H), 3.33 (t,J=6 Hz, 2H), 1.38 (t, J=7 Hz, 3H) ppm. ES MS M+1=361.

Step 3: Ethyl6-(4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate

To a solution of sodium1-(ethoxycarbonyl)-6-(4-fluorobenzyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-4-olate(1.45 g, 3.79 mmol) in DMF (20 mL) was added cesium carbonate (4.94 g,15.1 mmol). After 5 minutes, methyl iodide (2.15 g, 15.1 mmol) wasadded. The reaction mixture was stirred at room temperature. After 24hours, the product mixture was concentrated under vacuum. The residualmaterial was subjected to column chromatography on silica gel elutingwith 0-3% methanol in CH₂Cl₂. The appropriate fractions were combinedand concentrated to afford the N- and O-methylated compounds separately.

N-methylated compound: Ethyl6-(4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 7.27 (m, 2H), 7.02 (t, J=9 Hz, 2H), 4.69 (s,2H), 4.39 (q, J=7 Hz, 2H), 4.13 (s, 3H), 3.51 (s, 3H), 3.53 (t, J=6 Hz,2H), 2.59 (t, J=6 Hz, 2H), 1.38 (t, J=7 Hz, 3H) ppm. ES MS M+1=389.

O-methylated compound: Ethyl6-(4-fluorobenzyl)-3,4-dimethoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 7.31 (m, 2H), 7.03 (t, J=9 Hz, 2H), 4.73 (s,2H), 4.37 (q, J=7 Hz, 2H), 4.05 (m, 6H), 3.38 (t, J=6 Hz, 2H), 3.14 (t,J=6 Hz, 2H), 1.39 (t, J=7 Hz, 3H) ppm. ES MS M+1=389.

Step 4:6-(4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylicacid

To a solution of ethyl6-(4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate(1.15 g, 2.96 mmol) in 1:1:1 MeOH/H₂O/THF (15 mL) was added LiOH (0.37g, 8.88 mmol) and the solution was stirred for 2 hours. A solution of 1N HCl (8.9 mL) was added, the solution was concentrated and CHCl₃ and10% KHSO₄ were added. The layers were separated and the aqueous wasextracted repeatedly. The combined organic layers were filtered and thesolid collected. The remaining organic was dried over Na₂SO₄, filtered,combined with the collected solid and evaporated to give the crudeproduct.

¹H NMR (400 MHz, DMSO-d₆) δ 7.32 (dd, J=5.6, 8.6 Hz, 2H), 7.16 (t, J=8.8Hz, 2H), 4.64 (s, 2H), 3.84 (s, 3H), 3.42 (s, 3H), 3.4 (t, J=6 Hz, 2H),2.6 (t, J=6 Hz, 2H) ppm. ES MS M+1=361.

Step 5:6-(4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carbonylchloride

To6-(4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylicacid (0.213 g, 0.6 mmol) was added thionyl chloride (5 mL) and themixture was heated to reflux for 2 hours, then evaporated to dryness,suspended in toluene and evaporated three times to give the crudeproduct.

¹H NMR (400 MHz, CDCl₃) δ 7.30 (dd, J=5.3, 8.6 Hz, 2H), 7.03 (t, J=8.8Hz, 2H), 4.7 (s, 2H), 4.18 (s, 3H), 3.58 (s, 3H), 3.39 (t, J=6 Hz, 2H),2.65 (t, J=6 Hz, 2H)ppm.

ES MS M+1=379.

Step 6:5-amino-2-(4-fluorobenzyl)-8-methoxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione

To a solution of sodium azide (0.091 g, 1.4 mmol) in 2 mL water cooledto 0° C. was add6-(4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carbonylchloride (0.48 g, 1.28 mmol) in acetone (8 mL). The solution was stirredfor 30 minutes, then evaporated. The residue was partitioned betweenCHCl₃ and saturated Na bicarbonate, dried with Na₂SO₄, filtered andevaporated to give the crude product, which was chromatographed onsilica eluting with 5% MeOH/CHCl₃ saturated with NH₃.

¹H NMR (400 MHz, CDCl₃) δ 7.29 (dd, J=5.5, 8.4 Hz, 2H), 7.01 (t, J=8.6Hz, 2H), 4.7 (s, 2H), 4.05 (bs, 2H), 3.96 (s, 3H), 3.56 (s, 3H), 3.37(t, J=6 Hz, 2H), 2.42 (t, J=6 Hz, 2H) ppm. ES MS M+1=332.

Step 7:N-acetyl-N-[6-(4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]acetamide

To5-amino-2-(4-fluorobenzyl)-8-methoxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione(0.1 19 mg, 0.36 mmol) in a sealable microwave tube was added aceticanhydride (3.5 mL) and the solution was heated to 150° C. for 25 minutesin a microwave. The solution was evaporated to dryness to give the crudeproduct.

¹H NMR (400 MHz, CDCl₃) δ 7.29 (m, 2H), 7.02 (t, J=8.6 Hz, 2H), 4.69 (s,2H), 4.14 (s, 3H), 3.37 (s, 3H), 3.35 (t, J=6 Hz, 2H), 2.37 (t, J=6 Hz,2H), 2.32 (s, 6H)ppm.

ES MS M+1=416.

Step 8:N-[6-(4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]acetamide

ToN-acetyl-N-[6-(4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]acetamide(0.149 g, 0.36 mmol) in MeOH (5 mL) cooled to 0° C. was added 30% weightsolution NaOMe in MeOH (0.2 mL, 1.07 mmol). The reaction was warmed toroom temperature for 40 minutes, then 1 N HCl was added (1.07 mL) andthe reaction was concentrated, and CHCl₃ and 10% KHSO₄ were added. Thelayers were separated and the aqueous was extracted repeatedly. Theorganic layer was dried over Na₂SO₄, filtered, combined with thecollected solid and evaporated to give the crude product.

¹H NMR (400 MHz, CDCl₃) δ 8.46 (bs, 1H), 7.26 (m, 2H), 7.01 (t, J=8.6Hz, 2H), 4.65 (bs, 2H), 3.96 (s, 3H), 3.39 (s, 3H), 3.33 (t, J=6 Hz,2H), 2.45 (bs, 2H), 2.23 (s, 3H)ppm. ES MS M+1=374.

Step 9:N-[6-(4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]-N-methylacetamide

ToN-[6-(4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]acetamide(0.073 g, 0.196 mmol) in 2 mL DMF was added Cs₂CO₃ (0.084 g, 0.25 mmol)and methyl iodide (0.044 mL, 0.7 mmole) and the reaction was stirredovernight at room temperature. The solvent was removed and the residuewas partitioned between CHCl₃ and 10% KHSO₄, the organic was dried withNa₂SO₄, filtered and evaporated to give the crude product.

¹H NMR (400 MHz, CDCl₃) δ 7.30 (dd, J=5.4, 8.5 Hz, 2H), 7.03 (t, J=8.6Hz, 2H), 4.70 (s, 2H), 4.14 (s, 3H), 3.43 (s, 3H), 3.37 (m, 2H), 3.08(s, 3H), 2.48 (m, 2H), 1.87 (s, 3H) ppm. ES MS M+1=388.

Step 10:N-[6-(4-fluorobenzyl)-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]-N-methylacetamide

ToN-[6-(4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]-N-methylacetamide(0.070 g, 0.181 mmol) was dissolved in 1 mL glacial acetic acid and 0.75mL 30% by weight HBr in acetic acid solution was added. The reaction wasstirred for 1.5 hours, water was added and the reaction evaporated todryness under vacuum. The residue was purified on reverse phase and thefractions collected and evaporated. The residue was dissolved indioxane, from which crystals formed and were collected. The crystalswere dried under vacuum with heat to give the product.

¹H NMR (400 MHz, CDCl₃) δ 13.17 (s, 1H), 7.30 (dd, J=5.3, 8.7 Hz, 2H),7.03 (t, J=8.7 Hz, 2H), 4.73 (d, J=14.6 Hz, 1H), 4.66 (d, J=14.6 Hz,1H), 3.44 (s, 3H), 3.41 (m, 2H), 3.08 (s, 3H), 2.61 (m, 2H), 1.86 (s,3H) ppm.

ES MS M+1=374.

EXAMPLE 10 6-(4-Fluorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

Step 1: Methyl6-(4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate

To a solution of methyl6-(4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate(0.28 g, 0.81 mmol) in DMF (3.0 mL) was added Cs₂CO₃ (0.81 g, 2.47 mmol)at room temperature. After 10 minutes, CH₃I (0.597 g, 4.21 mmol) wasadded and the warmed to 40° C. After 2.5 hours, the product mixture waspartitioned between EtOAc and 1 N HCl. The organic extract was washedwith brine, dried with Na₂SO₄, filtered, and concentrated under vacuumto give a mixture of N,O- and O,O-alkylated products. The residualmaterial was subjected to column chromatography on silica gel elutingwith 0-3% methanol in CH₂Cl₂. The appropriate fractions were combinedand concentrated to afford the title compound.

¹HNMR (400 MHz, CDCl₃) δ 7.29 (m, 2h), 7.02 (t, J=9 Hz, 2H), 4.68 (s,2H), 4.12 (s, 3H), 3.91 (s, 3H), 3.48 (s, 3H), 3.32 (t, J=6 Hz, 2H),2.56 (t, J=6.5 Hz, 2H) ppm. ES MS M+1=375.

Step 2:6-(4-Fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylicacid

To a solution of methyl6-(4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate(0.575 g, 1.536 mmol) in methanol was added LiOH (0.11 g, 4.61 mmol) inwater. The reaction mixture was heated to reflux. After 0.5 hours, theproduct mixture cooled to room temperature and concentrated undervacuum. The residual material was partitioned between EtOAc and 1 N HCl.The organic extract was washed with brine, dried with Na₂SO₄, filtered,and concentrated under vacuum to provide the title compound.

¹HNMR (400 MHz, CDCl₃) δ 7.27 (m, 2h), 7.03 (t, J=9 Hz, 2H), 4.66 (s,2H), 3.95 (s, 3H), 3.49 (s, 3H), 3.35 (t, J=6 Hz, 2H), 2.68 (t, J=6 Hz,2H) ppm. ES MS M+1=361.

Step 3: 6-(4-Fluorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

To a solution of6-(4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylicacid (0.14 g, 0.40 mol) in DMF was added BOP (0.515 g, 1.167 mmol) andthe dimethylamine (2.0 M in THF) (0.035 g, 0.778 mmol). After 24 hours,the product mixture was concentrated under vacuum. The residual materialwas purified using reverse phase HPLC eluting with 5-95% acetonitrile(0.1% TFA) in H₂O (0.1% TFA) to give 6-(4-fluorobenzyl)-4-methoxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide(ES MS M+1=388). A solution of this product (0.1 g, 0.3 mmol) in CH₂Cl₂was treated with HBr (30 wt % in acetic acid) (0.104 g, 1.29 mmol) andafter stirring at room temperature for 24 hours, concentrated undervacuum. The residual material was purified using reverse phase HPLCeluting with 5%-95% acetonitrile (0.1% TFA) in H₂O (0.1% TFA) to affordthe title compound.

¹HNMR (400 MHz, CD₃OD) δ 7.38 (m, 2H), 7.04 (t, J=9 Hz, 2H), 4.81 (d,J=14.8 Hz, 1H), 4.56 (d, J=14.8 Hz, 1H), 3.49 (t, J=6 Hz, 2H), 3.43 (s,3H), 3.08 (s, 3H), 2.93 (s, 3H), 2.59 (t, J=6 Hz, 2H) ppm.

ES MS M+1=374.

The compounds in the following table were prepared in accordance withthe procedure set forth in Example 10, using the appropriate amine inplace of the dimethylamine employed in Step 3 of Example 10. When thecompound was prepared as a salt, the identity of the salt is included inparentheses following the compound name for the free base.

ES MS Example R^(G) Name (M + 1) 10-2

N-cyclobutyl-6-(4-fluorobenzyl)-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 400.2 10-3

N-cyclopropyl-6-(4-fluorobenzyl)-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 386.1 10-4

6-(4-fluorobenzyl)-4-hydroxy-N-isopropyl-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6- naphthyridine-1-carboxamide388.1 10-5

6-(4-fluorobenzyl)-4-hydroxy-2-methyl-3,5-dioxo-N-(2,2,2-trifluoroethyl)-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 428.1 10-6

6-(4-fluorobenzyl)-4-hydroxy-2-methyl-N-[2-(methylsulfonyl)ethyl]-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 452.2 10-7

N,6-bis(4-fluorobenzyl)-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6- naphthyridine-1-carboxamide 454.210-8

2-(4-fluorobenzyl)-8-hydroxy-6-methyl-5-(piperidin-1-ylcarbonyl)-2,3,4,6-tetrahydro- 2,6-naphthyridine-1,7-dione414.1 10-9

6-(4-fluorobenzyl)-4-hydroxy-2-methyl-N-neopentyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 416.1 10-10

2-(4-fluorobenzyl)-8-hydroxy-5- (thiomorpholin-4-ylcarbonyl)-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione 418.3 10-11

2-(4-fluorobenzyl)-8-hydroxy-5-(piperazin-1-ylcarbonyl)-2,3,4,6-tetrahydro-2,6- naphthyridine-1,7-dione (TFA salt)401.1 10-12¹

4-{[6-(4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]carbonyl}-N,N-dimethylpiperazine-1- sulfonamide 508.0 10-13²

2-(4-{[6-(4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]carbonyl}piperazin-1-yl)- N,N-dimethyl-2-oxoacetamide500.1¹Example 10-12 can also be prepared via sulfonylation of Example 10-11with dimethylaminosulfonyl chloride prior to deprotection with HBr.²Example 10-13 can also be prepared via acylation of Example 10-11 withdimethylaminooxalylchloride prior to deprotection with HBr.

EXAMPLE 116-(3-Chloro-4-fluorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

Step 1: 6-(4-methoxybenzyl)-4-methoxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

In a manner similar to that described for6-(4-fluorobenzyl)-4-methoxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide(Example 10, Step 3), 6-(4-methoxybenzyl)-4-methoxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine1-carboxamide was prepared starting from p-methoxybenzyl chloride, andthe material was purified using reverse phase HPLC eluting with 5%-95%acetonitrile (0.1% TFA) in H₂O (0.1% TFA).

¹HNMR (400 MHz, CDCl₃) δ 7.22 (d, J=8.6 Hz, 2H), 6.84 (d, J=8.6 Hz, 2H),4.82 (d, J=14.5 Hz, 1H), 4.46 (d, J=14.5 Hz, 1H), 4.07 (s, 3H), 3.78 (s,3H), 3.45 (s, 3H), 3.40 (m, 1H), 3.30 (m, 1H), 3.09 (s, 3H), 2.90 (s,3H), 2.51 (m, 1H), 2.35 (m, 1H) ppm. (ES MS M+1=400.1)

Step 2:4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

A solution of 6-(4-methoxybenzyl)-4-methoxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide(0.18 g, 0.45 mmol) in toluene (about 3 mL) was treated with p-toluenesulfonic acid (0.34 g, 1.8 mmol). The mixture was heated to 110° C. for4 hours, then cooled and concentrated under vacuum. The residue waspartitioned between water and EtOAc, the aqueous layer concentrated, andthe residue purified by reverse phase chromatography to give the titleproduct.

¹HNMR (400 MHz, CD₃OD) δ 3.44 (m, 5H), 3.10 (s, 3H), 2.97 (s, 3H), 2.60(t, J=6.6 Hz, 2H) ppm.

(ES MS M+1=266.2)

Step 3:6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

A solution of4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide(0.018 g, 0.068 mmol) in DMF (2 mL) was treated with Cs₂CO₃ (0.066 g,0.2 mmol) and 3-chloro-4-fluoro benzyl bromide (0.045 g, 0.2 mmol) andheated to 40° C. The reaction mixture was then cooled to 0 degrees C., asuspension of NaH (95% dispersion in oil, 0.2 mmol) was added and thereaction was warmed to room temperature. After 1 hr the reaction waspartitioned between ice water and EtOAc, the organic layer was driedwith brine and Na₂SO₄, filtered and evaporated to give6-(3-chloro-4-fluorobenzyl)₄-[(3-chloro-4-fluorobenzyl)oxy]-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide(ES MS M+1=549.9). This material was then dissolved in CH₂Cl₂ (3 mL) andtreated with 4 drops of a 30% by weight solution of HBr in propionicacid at room temperature. After 20 minutes the solution was concentratedand purified by reverse phase chromatography to give the product.

¹HNMR (400 MHz, CD₃OD) δ 7.48 (m, 1H), 7.32 (m, 1H), 7.22 (t, J=8.5 Hz,1H), 4.76 (d, J=14.8 Hz, 1H), 4.63 (d, J=14.8 Hz, 1H), 3.50 (t, J=6.4Hz, 2H), 3.44 (s, 3H), 3.08 (s, 3H), 2.95 (s, 3H), 2.61 (t, J=6.2 Hz,2H) ppm. (ES MS M+1=407.9)

EXAMPLE 126-(3-Chloro-4-fluorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

Step 1: 1-(3-Chloro-4-fluorobenzyl)piperidin-2-one

Valerolactam (153.3 g, 1.54 mol) was dissolved in NMP (3.5 L) and cooledto 0° C. NaH (67.7 g, 1.69 mol, 60% dispersion in oil) was added inportions over 5 minutes keeping the temperature at 0° C. The reactionwas stirred for 30 minutes, and 3-chloro-4-fluorobenzylbromide (345.5 g,1.54 mol) dissolved in 200 mL NMP was added over 30 minutes, againkeeping the internal temperature at 0° C. The reaction was aged for 1hour at 0° C., and allowed to warm to room temperature overnight. LCMSshowed the reaction complete. The reaction mixture was quenched with 5 Ldistilled H₂O, extracted with 3 portions of CH₂Cl₂ (2 L, 1 L, 1 L) andthe organic layers combined and washed with three 4 L portions of water.The organic layer was concentrated and was found to contain NMP. Theresidual oil was dissolved in EtOAc (4 L), and extracted with three 2 Lportions of water. The organic layer was concentrated to give theproduct that solidified upon standing.

¹H NMR (400 MHz, CDCl₃) δ 7.24 (m, 2H), 7.0 (m, 2H), 7.1 (m, 1H), 4.56(s, 2H), 3.19 (t, J=4.9, 2H), 2.46 (t, J=6.4, 2H), 1.8-1.75 (m, 4H) ppm.

Step 2: 1-(3-Chloro-4-fluorobenzyl)-5,6-dihydropyridin-2(1H)-one

1-(3-Chloro-4-fluorobenzyl)piperidin-2-one (340 g, 1.41 mol) wasdissolved in THF (5 L) and cooled to −20° C. under nitrogen. LHMDS (3.09L, 3.09 mol, 1M in THF) was added over 40 minutes keeping thetemperature at −20° C. and aged for 1 hr at −20° C. The methyl benzenesulfonate (231 mL, 1.69 mol) was added over 30 minutes, again keepingthe internal temperature at −20° C. The reaction was aged for 30 minutesat −20° C. and LCMS showed the reaction complete. The reaction mixturewas diluted with 4 L EtOAc and washed with four 2 L portions ofdistilled H₂O. The organic layer was concentrated and the residue wasdissolved in 4 L toluene. Na₂CO₃ (500 g) was added and the reactionheated to 100° C. for 1 hour. LCMS showed the reaction complete. Theresidue was diluted with 4 L EtOAc and washed with four 2 L portions ofdistilled water. The organic layer was concentrated and the residuepurified by flash chromatography on silica eluting with a gradient of0-60% EtOAc/heptane. The product was isolated as an oil.

¹H NMR (400 MHz, CDCl₃) δ 7.3 (m, 1H), 7.15 (m, 1H), 7.1 (t, 1H), 6.6(m, 1H), 6.0 (m, 1H), 4.55 (s, 2H), 3.33 (t, 2H), 1.38 (m, 2H) ppm. (ESMS M+1=240.13)

Step 3: 2-Butoxy-2-oxoethanaminium chloride

Glycine hydrochloride (400 g, 3.58 mol) was suspended in 8 L ofn-butanol and thionyl chloride (1.37 L, 18.84 mol) was added slowlydropwise (exotherm). After addition was complete, the reaction washeated to 70° C. overnight. The reaction could be followed by spottingdirectly on TLC, pumping off the volatiles, eluting with 10% MeOH/CHCl₃saturated with NH₃, and staining in ninhydrin. The next day the reactionwas stripped to dryness under vacuum and the residue was triturated withheptane/EtOAc to give the product as a white solid after drying on afilter under Nitrogen.

¹H NMR (400 MHz, CDCl₃) δ 8.5 (bs, 3H), 4.18 (t, J=6.7 Hz, 2H), 4.0 (bs,2H), 1.62 (m, 2H), 1.38 (m, 2H), 0.92 (t, J=7.4 Hz, 3H) ppm. ES MSM+1=132.

Step 4: Butyl N-[ethoxy(oxo)acetyl]glycinate

2-Butoxy-2-oxoethanaminium chloride (573.5 g, 3.42 mol) was suspended in7 L of ethanol and triethylamine (415 g, 4.1 mol) was added.Diethyloxalate (1.0 Kg, 6.8 mol) was added and the reaction warmed to50° C. for 3 hours. The reaction was cooled, the volatiles were removedunder vacuum and the residue was dissolved in methylene chloride andwashed with two 4 L portions of water and dried over MgSO₄. The next daythe reaction was filtered, evaporated to give ˜1.2 Kg of an oil that waschromatographed on silica eluting with Heptane/EtOAc to give product.

¹H NMR (400 MHz, CDCl₃) δ 7.56 (bs, 1H), 4.37 (q, J=7.2 Hz, 2H), 4.2 (t,J=6.6 Hz, 2H), 4.12 (d, J=5.5 Hz, 2H), 1.64 (p, J=6.8 Hz, 2H), 1.39 (t,J=7.15 Hz, 3H), 1.37 (m, buried, 2H), 0.94 (t, J=7.4 Hz, 3H) ppm. ES MSM+1=232.

Step 5: Ethyl 5-butoxy-1,3-oxazole-2-carboxylate

Butyl N-[ethoxy(oxo)acetyl]glycinate (783 g, 3.38 mol) was dissolved in8 L of acetonitrile in a 50 L Chemglass reactor with overhead stirrerand P₂O₅ (415 g, 2.92 mol) was added in large portions, watching forexotherm. The reaction was heated to 60° C. for 1 hour and LCMS showedthe reaction done. After cooling, water (8 L) was added at 20° C. andthe reaction was transferred to a 50 L flask. Methylene chloride (8 L)was added, the layers split and the aqueous layer was extracted withthree 2 L volumes of methylene chloride. The combined organic layerswere washed with two 4 L portions of saturated aqueous NaHCO₃, thendried with MgSO₄ and evaporated to give an oil that was purified onsilica eluting with 0-30% EtOAc/heptane to give the product as an oil.

¹H NMR (400 MHz, CDCl₃) δ6.33 (s, 1H), 4.42 (q, J=7.15 Hz, 2H), 4.18 (t,J=6.4 Hz, 2H), 1.8 (p, J=6.4 Hz, 2H), 1.47 (p, J=7.4 Hz, 2H), 1.41 (t,J=7.15 Hz, 3H), 0.97 (t, J=7.4 Hz, 3H) ppm. ES MS M+1=214.

Step 6: Ethyl6-(3-chloro-4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate

Ethyl 5-butoxy-1,3-oxazole-2-carboxylate (44.5 g, 208.6 mmol) and1-(3-chloro-4-fluorobenzyl)-5,6-dihydropyridin-2(1H)-one (25 g, 104.3mmol) were placed in a heavy walled round bottom flask equipped with ascrew top and acid resistant O-ring and a stir bar. The mixture wasstirred and water (2.82 mL, 156.7 mmol) was added. The reaction wassealed and placed in an oil bath pre-heated to 130° C. The reaction wasaged for 72 hours, when LCMS showed much of the lactam had beenconsumed. The reaction was allowed to cool and sit until the mass hadsolidified. The mass was taken up in ether and the solids collected byfiltration to give the product as a tan solid. The product was furtherpurified by crystallization from EtOAc.

¹H NMR (400 MHz, CDCl₃) δ 12.79 (s, 1H), 8.42 (s, 1H), 7.4 (dd, J=2, 7Hz, 1H), 7.2 (m, 1H), 7.15 (t, J=8.6 Hz, 1H), 4.7 (s, 2H), 4.4 (q, J=7Hz, 2H), 3.5 (m, 4H), 1.4 (t, J=7 Hz, 3H) ppm. (ES MS M+1=379.0)

Step 7: Ethyl6-(3-chloro-4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate2-oxide

Ethyl6-(3-chloro-4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate(22 g, 58 mmol) was dissolved in 500 mL glacial acetic acid and H₂O₂(30% by weight in water, 65.8 mL) was added. The reaction was warmed to100° C. and aged for four hours at which time LCMS showed the reactiondone. The solution was cooled in an ice bath to 25° C. and treated withsaturated Na₂SO₃ solution, keeping the temperature below 40° C. Whenstarch paper test showed no peroxides present, the solution wasconcentrated by ⅓, the pH was adjusted to ˜3 with aqueous HCl and thesolution extracted with CH₂Cl₂ several times. The organic layers weredried over Na₂SO₄, filtered and evaporated to give product as an oil.

¹H NMR (400 MHz, CDCl₃) δ 12.65 (s, 1H), 7.9 (s, 1H), 7.38 (dd, J=2, 7Hz, 1H), 7.27-7.1 (m, 2H), 4.66 (s, 2H), 4.44 (q, J=7 Hz, 2H), 3.52 (t,J=7 Hz, 2H), 2.90 (t, J=7 Hz, 2H), 1.38 (t, J=7 Hz, 3H) ppm. (ES MSM+1=395.0)

Step 8: Ethyl3,4-bis(acetyloxy)-6-(3-chloro-4-fluorobenzyl)-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate

Ethyl6-(3-chloro-4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate2-oxide (23 g, 58 mmol) was dissolved in 400 mL acetic anhydride andheated with stirring under nitrogen to 100° C. for 1 hour. By LCMS, thestarting material and product are very close in retention time. To checkthat the reaction was done, an aliquot was treated with NaOMe in waterand CH₃CN. The resulting hydrolyzed product elutes at an earlierretention time and allows distinguishing between remaining N-oxide andrearranged product. The reaction was evaporated to give the crudeproduct as an oily residue that was taken on to the next step.

¹H NMR (400 MHz, CDCl₃) δ 7.36 (m, 1H), 7.2-7.1 (m, 1H), 7.12 (t, J=8Hz, 1H), 4.68 (bs, 2H), 4.4 (q, J=7 Hz, 2H), 3.48 (m, 2H), 3.35 (m, 2H),2.38 (bs, 6H), 1.4 (t, J=7 Hz, 3H) ppm. (ES MS M+1=394.9)

Step 9: Methyl6-(3-chloro-4-fluorobenzyl)-3,4-dihydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate

Ethyl3,4-bis(acetyloxy)-6-(3-chloro-4-fluorobenzyl)-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate(27.8 g, 58 mmol) was dissolved in 300 mL MeOH and treated with a 30% byweight solution of NaOMe in MeOH (41.8 mL, 232 mmol, 4 equivalents wassufficient to get the pH of the reaction to 9) for 5 hours at 40° C.LCMS showed the cleavage of the acetate groups was complete, a littletransesterification was observed as well. The volume was reduced by halfunder vacuum and the mixture was diluted with THF (400 mL) and anadditional 33 mL of NaOMe was added. The reaction was stirred at roomtemperature overnight and then warmed to 50° C. for four hours, whenLCMS showed transesterification completed. The reaction was neutralizedwith 1N HCl and allowed to sit at room temperature overnight, then lateracidified to pH 3 and extracted with CHCl₃ several times. The organiclayer was dried over Na₂SO₄ and evaporated to give a black oil.

¹H NMR (400 MHz, CDCl₃) δ 10.0-8.2 (bs, 1H), 7.38 (dd, J=6.8.2 Hz, 1H),7.2 (m, 1H), 7.13 (t, J=8.4 Hz, 1H), 4.68 (s, 2H), 3.92 (s, 3H), 3.46(t, J=6.4 Hz, 2H), 3.34 (t, J=6.4 Hz, 2H) ppm. (ES MS M+1=380.9)

Step 10: Methyl6-(3-chloro-4-fluorobenzyl)-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate

To a solution of methyl6-(3-chloro-4-fluorobenzyl)-3,4-dihydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate(18.00 g, 47 mmol) in DMF (200 mL) was added magnesium methylate (96.08mL, 95 mmol), and the reaction was warmed for 1 hour and cooled. Thereaction was treated with iodomethane (17.66 mL, 283 mmol) and stirredat 45° C. overnight. At this time, LCMS showed the reaction incomplete,and an additional equivalent of iodomethane (2.95 mL, 48 mmol) wasadded. The reaction was again stirred for 4 hours. The solvent wasremoved in vacuo, and the resulting oil was partitioned betweenchloroform and 1N HCl. The aqueous layer was washed twice more withchloroform. The organic fractions were extracted with 10% sodiumbisulfite, and the bisulfite layer was washed twice with chloroform. Thecombined organic layers were washed with 5% aqueous HCl and brine, driedover sodium sulfate and concentrated in vacuo to afford the product as ablack oil. This material appears quite clean by NMR and HPLC, but ishighly colored.

¹H NMR (400 MHz, CDCl₃) δ 13.37 (s, 1H), 7.35 (dd, J=2.4, 6.9 Hz, 1H),7.22-7.18 (m, 1H), 7.13 (t, J=8.4 Hz, 1H), 4.67 (s, 2H), 3.92 (s, 3H),3.54 (s, 3H), 3.43 (t, J=6.4 Hz, 2H), 2.81 (t, J=6.4 Hz, 2H) ppm. (ES MSM+1=395.0)

Step 11: Methyl6-(3-chloro-4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate

To a solution of methyl6-(3-chloro-4-fluorobenzyl)-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate(7.25 g, 18 mmol) in anhydrous DMF (75 mL) was added cesium carbonate(5.98 g, 18 mmol) and iodomethane (2.86 mL, 46 mmol). The reaction wasstirred at room temperature overnight, and LCMS showed 70% completion.The reaction was heated to 50° C. for 7 hours and then allowed to stirat room temperature again overnight. LCMS indicated completion. Thereaction was concentrated to dryness, and the resulting residue wasdissolved in chloroform. The solution was extracted twice with saturatedNa₂SO₃ solution, dried over sodium sulfate, filtered, and evaporated toafford a dark brown oil.

¹H NMR (400 MHz, CDCl₃) δ 7.34 (dd, J=2.1, 7.0 Hz, 1H), 7.19 (m, 1H),7.11 (m, 1H), 4.65 (s, 2H), 4.12 (s, 3H), 3.92 (s, 3H), 3.49 (s, 3H),3.34 (m, 2H), 2.59 (m, 2H) ppm. (ES MS M+1=409.0)

Step 12:6-(3-Chloro-4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylicacid

To a solution of methyl6-(3-chloro-4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate(14.3 g, 35 mmol) in THF (1501 mL) and MeOH (150 mL) was added LiOH(2.74 g, 114 mmol) dissolved in 114 mL water and the reaction was heatedto 50° C. for 45 minutes. HPLC showed completion. The reaction wasneutralized with 1N HCl and cooled to room temperature. THF was removedin vacuo, and the resulting slurry was partitioned between CHCl₃ and 5%aqueous HCl. The aqueous was washed with additional CHCl₃. The combinedorganics were dried over sodium sulfate, filtered, and concentrated todryness to afford the desired product as a pale yellow foam. Thematerial was crystallized from ethyl acetate to give a light yellowsolid.

¹H NMR (400 MHz, CD₃OD) δ 7.49 (dd, J=2.0, 6.8 Hz, 1H), 7.34-7.30 (m,1H), 7.25-7.20 (m, 1H), 4.71 (s, 2H), 3.98 (s, 3H), 3.58 (s, 3H), 3.50(m, 2H), 2.77-2.74 (m, 2H) ppm. (ES MS M+1=395.0)

Step 13:6-(3-Chloro-4-fluorobenzyl)-4-methoxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

To a suspension of6-(3-chloro-4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylicacid (8.50 g, 22 mmol) in methylene chloride (300 mL) at 0° C. was addedoxalyl chloride (2.25 mL, 26 mmol) and 1 drop of anhydrous DMF. Thereaction was stirred at 0° C. for 15 minutes during which time nobubbling was observed. The reaction was then allowed to warm to roomtemperature and stirred for 40 minutes. At this time bubbling hadceased, and all material was in solution. An aliquot of the solution wasquenched with dimethylamine and checked by LCMS to confirm completion.To the solution of the acid chloride starting material at 0° C. wasadded dimethylamine in THF (43.56 mL, 87 mmol, 2.0 M). The green/yellowreaction was allowed to stir at room temperature overnight although thereaction appeared to proceed immediately by LCMS. The solvent wasremoved in vacuo, and the resulting residue was dissolved in chloroform.The solution was washed with water and 5% aqueous HCl solution and backextracted to recover the product. The combined organic layers werewashed with brine, dried over sodium sulfate, filtered and concentratedin vacuo. The resulting iridescent green/yellow residue was examined inseveral TLC solvent systems (95:5 CH₂Cl₂:MeOH, 2:1 acetone:hexanes, 1:1EtOAc:hexanes) with the most efficient separation of some early runningimpurities achieved in the CH₂Cl₂:MeOH system. The material was purifiedby silica gel flash column chromatography, loaded as a solution inmethylene chloride onto a 330 g RediSep column. Gradient elutionconsisted of 1.5 L each of neat CH₂Cl₂, 1% MeOH:CH₂Cl₂, 2% MeOH:CH₂Cl₂,3% MeOH:CH₂Cl₂, 4% MeOH:CH₂Cl₂, and 5% MeOH:CH₂Cl₂, in sequential order.The desired material began to elute with 3% and was pushed off thecolumn with 4% and 5%, yielding two sets of fraction. The earlier setafforded of the desired product plus a fluorescent green contaminant.The later set afforded clean material.

¹H NMR (400 MHz, CD₃OD) δ 7.49 (dd, J=2.0, 7.2 Hz, 1H), 7.34-7.31 (m,1H), 7.22 (t, J=8.8 Hz, 1H), 4.77 (d, J=15.2 Hz, 1H), 4.65 (d, J=15.2Hz, 1H), 3.97 (s, 3H), 3.52-3.48 (m, 2H), 3.45 (s, 3H), 3.11 (s, 3H),2.97 (s, 3H), 2.57-2.54 (m, 2H) ppm. (ES MS M+1=422.0)

Step 14:6-(3-Chloro-4-fluorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxaamide

To6-(3-chloro-4-fluorobenzyl)-4-methoxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide(5.43 g, 13 mmol) was added 33% HBr in acetic acid (20 mL, 129 mmol),and the mixture was heated to 50° C. for 15 minutes to give a thick,pale brown/orange solution. By LCMS, the reaction was complete, and theacetic acid was removed in vacuo. The resulting residue was partitionedbetween chloroform and water, and the organic layer was then washed withaqueous sodium sulfite solution and brine. The combined organic extractswere dried over sodium sulfate, filtered, and concentrated in vacuo toafford a pale yellow foam. The foam was dissolved in hot isopropanol andcrystallized quickly, and the crystals were collected by filtration. Thematerial was then taken up in hot acetone which did not afford acomplete solution, so the mixture was hot filtered. The resultingfiltrate was allowed to cool causing crystals to form. The insolublematerial from the hot acetone filtration was dissolved in hot ethanoland re-filtered. This resulting filtrate also produced large, slowlygrown crystals over the course of one day. The crystals compound freebase from both filtrates were collected, combined, dried for 4 hours,milled, and re-dried overnight without heat to give product.

¹H NMR (400 MHz, CD₃OD) δ 7.51 (dd, J=2.1, 7.2 Hz, 1H), 7.36-7.33 (m,1H), 7.23 (t, J=8.9 Hz, 1H), 4.79 (d, J=14.8 Hz, 1H), 4.65 (d, J=14.8Hz, 1H), 3.52 (t, J=6.8 Hz, 2H), 3.46 (s, 3H), 3.10 (s, 3H), 2.97 (s,3H), 2.64 (t, J=6.8 Hz, 2H) ppm. (ES MS exact mass=408.1113)

Step 15:6-(3-Chloro-4-fluorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamidesodium salt

To6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide(1.08 g, 2.65 mmol) in a freeze drying flask was added acetonitrile (5mL) at room temperature. The flask was placed in an ultrasonic bath atroom temp for 1 minute. Some crystals remained. Water was added (5 mL)followed by the 1 N NaOH (2.65 mL, 2.65 mmol). The total was placed inthe ultrasonic bath for 1 minute. An additional 1 mL of acetonitrile wasadded and placed in the ultrasonic bath for an additional minute. Allmaterial was now dissolved. More water (30 mL) was added to the flaskand all stayed soluble. The contents of the flask were frozen withspinning in a −78° C. acetone/dry ice bath and placed on the freezedrier for 40 hours to give the product as a dry fluffy solid.

¹H NMR (400 MHz, CD₃OD) δ 7.46 (dd, J=2.2, 7.14 Hz, 1H), 7.33-7.29 (m,1H), 7.17 (t, J=9.0 Hz, 1H), 4.72 (d, J=14.8 Hz, 1H), 4.65 (d, J=14.8Hz, 1H), 3.35 (s, 3H), 3.33-3.96 (m, 2H), 3.07 (s, 3H), 2.97 (s, 3H),2.47 (dd, J=5.68,11.36 Hz, 2H) ppm. (ES MS M+1=408.0)

EXAMPLE 136-(3-Chloro-4-fluorobenzyl)-4-hydroxy-2-isopropyl-N,N-dimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

Step 1:6-(3-Chloro-4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylicacid

To a solution of ethyl6-(3-chloro-4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate(27.0 g, 71 mmol) in THF (333 mL) and MeOH (166 mL) was added LiOH (5.21g, 214 mmol) dissolved in enough water to make a 1N solution (totalvolume 213 mL) and the reaction was heated to 60° C. overnight. HPLCshowed completion. A white precipitate was observed. The reaction wasneutralized with 1N HCl and the more volatile solvents removed, leavingthe water solution. 300 mL water was added the solution was acidified topH 1 with 1 N HCl. A large amount of solids had precipitated. Theresulting slurry was stirred vigorously with 100 mL CHCl₃. Most of thesolid had precipitated from the partitioning and the entire mix wasfiltered and dried over the weekend to give product. Additional lesspure product was recovered from extraction of the filtrate.

¹H NMR (400 MHz, CD₃OD) δ 8.25 (s, 1H), 7.53(dd, J=2.2, 6.9 Hz, 1H),7.36 (m, 1H), 7.23 (t, J=8.9 Hz, 1H), 4.74 (s, 2H), 3.61(bt, J=6.4 Hz,1H), 3.50(bt, J=6.4 Hz, 1H) ppm. (ES MS M+1=351.0)

Step 2:6-(3-Chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide

To a suspension of6-(3-chloro-4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylicacid (25.0 g, 71.3 mmol) in methylene chloride (1000 mL) at 0° C. wasadded oxalyl chloride (12.4 mL, 143 mmol) and 8 drops of anhydrous DMF.The reaction was stirred at 0° C. for 15 minutes. during which time nobubbling was observed. The reaction was then allowed to warm to roomtemperature and stirred for 40 minutes. At this time bubbling hadceased. An aliquot of the solution was quenched with dimethylamine andchecked by LCMS. The reaction was incomplete. An additional 0.5equivalent of oxalyl chloride was added and the reaction stirred anadditional 40 minutes. The reaction never attained complete solution butwas complete by LCMS. To the suspension of the acid chloride cooled to0° C. was slowly added 2M dimethylamine in THF (140.8 mL, 281 mmol). Therate of addition was adjusted to avoid a large exotherm. The pH of thesolution was found to be about 9. The yellow reaction was allowed tostir at room temperature overnight although the reaction appeared toproceed immediately by LCMS. The solvent was removed in vacuo, and theresulting residue was dissolved in chloroform. The solution was washedwith water and 5% aqueous HCl solution and the aqueous layer backextracted to recover the product. The combined organic layers werewashed with brine, dried over sodium sulfate, filtered and concentratedin vacuo to give a brown/yellow waxy solid. The initial NMR shows anexcessive number of methyl group peaks, perhaps as a result of oxalylchloride reacting with dimethylamine. A small sample was purified byreverse phase chromatography eluting with 95:5-5:95 water/acetonitrile0.1% TFA to give clean material for NMR.

¹H NMR (400 MHz, CDCl₃) δ 12.35 (bs, 1H), 10.9 (bs, 1H), 8.32 (s, 1H),7.38 (dd, J=2.0, 6.7 Hz, 1H), 7.22 (m, 1H), 7.14 (t, J=8.5 Hz, 1H), 4.69(s, 2H), 3.54 (t, J=6.8 Hz, 2H), 3.14 (s, 3H), 3.05 (t, J=6.8 Hz, 2H),2.95 (s, 3H) ppm. (ES MS M+1=378.1)

Step 3:6-(3-Chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide2-oxide

6-(3-Chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide(24 g, 63.5 mmol) was dissolved in 1000 mL glacial acetic acid andper-acetic acid (32% by weight in acetic acid, 151 mL, 635 mmol) andsodium acetate (2.6 g, 31.7 mmol) was added. The reaction was warmed to50° C. and aged overnight at which time LCMS showed the reaction done.The solution reduced in volume to ⅓ on the rotoevaporator, cooled in anice bath and quenched slowly with 10% Na₂SO₃ solution until no peroxidewas detected by a starch paper test. The reaction was transferred to aseparatory funnel and water (500 mL) and chloroform was added. Thelayers were separated and the water extracted with CHCl₃ several times.The combined organic layers were washed with slightly acidic water,brine and dried over Na₂SO₄, filtered and evaporated to give the productas an oil. The initial NMR shows an excessive number of methyl grouppeaks, perhaps as a result of oxalyl chloride reacting withdimethylamine in the second step and this impurity being carriedthrough. A small sample was purified by reverse phase chromatographyeluting with 95:5-5:95 water/acetonitrile 0.1% TFA to give cleanmaterial for NMR.

¹H NMR (400 MHz, CDCl₃) δ 12.75 (bs, 1H), 8.4 (bs, 2H), 8.1 (s, 1H),7.37 (dd, J=1.9, 6.9 Hz, 1H), 7.20 (m, 1H), 7.15 (t, J=8.5 Hz, 1H), 4.84(d, J=14.7 Hz, 1H), 4.51 (d, J=14.7 Hz, 1H), 3.61 (m, 1H), 3.59 (m, 1H),3.15 (s, 3H), 3.05 (m, 1H), 2.93 (s, 3H), 2.74 (m, 1H) ppm. (ES MSM+1=394.1)

Step 4:6-(3-Chloro-4-fluorobenzyl)-1-[(dimethylamino)carbonyl]-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-3,4-diyldiacetate

6-(3-Chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide2-oxide (25 g, 63.5 mmol) was dissolved in 24 mL acetic anhydride andheated with stirring under nitrogen to 100° C. for 16 hours. By LCMS,the starting material and product are close in retention time and appearas the same molecular weight. To check that the reaction was done, analiquot was treated with NaOMe in water and CH₃CN. The resultinghydrolyzed product elutes at an earlier retention time and allowsdistinguishing between remaining N-oxide and rearranged product. Thereaction was evaporated and the residue was partitioned betweenchloroform and water and the water layer was back-extracted with morechloroform. The aqueous layer was checked by LCMS for product and nolonger contained any. The organic layers were combined, dried overNa₂SO₄, filtered and evaporated to give an oil. (ES MS M+1 of NaOMetreated aliquot=394.0)

Step 5:6-(3-Chloro-4-fluorobenzyl)-3,4-dihydroxy-N,N-dimethyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide

6-(3-Chloro-4-fluorobenzyl)-1-[(dimethylamino)carbonyl]-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-3,4-diyldiacetate (30 g, 62.7 mmol) was dissolved in 500 mL MeOH and treatedwith a 30% by weight solution of NaOMe in MeOH (45.2 mL, 251 mmol 4equivalents was sufficient to get the pH of the reaction to 9) for 1hour at 40° C. LCMS showed the cleavage of the acetate groups wascomplete. The reaction was neutralized with 1N HCl and the volumereduced to remove the MeOH and the residue was diluted with water andacidified to pH 3. The cloudy aqueous layer was diluted with an equalvolume (800 mL) of chloroform. After shaking, the product began tocrystallize out of the solutions and gathered at the miniscus. The totalcontents of the funnel were filtered and the collected solids werewashed with water until no more salts appeared to remain. The solid wasdried in vacuo for 16 hours to give a cinnamon colored solid. Theorganic layer from the filtered extraction was collected, washed withwater and dried over Na₂SO₄, filtered and evaporated. The residue wascrystallized from methanol to give product. The crude material was quiteinsoluble but was crystallized from DMF, then boiled in MeOH, filteredand dried under vacuum to give product.

¹H NMR (400 MHz, DMSO) δ 13.0 (s, 1H), 11.9 (s, 1H), 7.58 (d, J=6.9 Hz,1H), 7.38 (m, 2H), 4.69 (bs, 2H), 3.49 (m, 2H), 2.91 (s, 3H), 2.84 (s,3H), 2.56 (bs, 2H), ppm. (ES MS M+1=394.0)

Step 6:6-(3-Chloro-4-fluorobenzyl)₆₄-hydroxy-2-isopropyl-N,N-dimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

To a solution of6-(3-chloro-4-fluorobenzyl)-3,4-dihydroxy-N,N-dimethyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide(3.00 g, 7.62 mmol) in DMSO (86 mL) was added magnesium methylate (42.75mL of a 6-10% methanol solution, 24.4 mmol), and the reaction was heatedto 60° C. for 0.75 hour. The reaction mixture was reduced on arotoevaporator to remove all of the MeOH over 45 minutes. The heat gunwas used to drive all MeOH from the bump bulb. The reaction was treatedwith 2-iodopropane (2.84 mL, 38.1 mmol) and allowed to stir at 60° C.for 3 hours. LCMS showed 11% starting material remaining and over 70%conversion to N- and O-alkylated products (typically 2:1). The reactionwas diluted with 350 mL EtOAc to which 125 mL 1N HCl was added, and thephases were separated. The aqueous layer was washed once with methylenechloride (100 mL). The combined organic layers were washed with 1N HCltwice more and the organic layer was isolated. The organic layer waswashed with 10% aqueous solution of NaHSO₃ (3×100 mL) followed by brine.The organic layer was dried over sodium sulfate and concentrated invacuo to afford a yellow-orange foam residue. The solid combined withadditional crude material from other reactions, dissolved in DMSO andMethanol and purified via reverse phase chromatography using a Biotage75 L canister and a Varian Metaflash 75 L C-18 column, eluting with agradient of 70:30 to 35:65 A:B where A=0.05% TFA in water and B=0.05%TFA in acetonitrile (flowrate=300 mL/minute, detection at 214 and 254nM). Evaporation of the fractions afforded pure oil by HPLC/LCMS andNMR. Crystallization from EtOAc:hexane afforded white, analytically pureproduct.

¹H NMR (400 MHz, CD₃OD) δ 7.50 (dd, J=1.9, 7.2 Hz, 1H), 7.32 (m, 1H),7.22 (t, J=8.8 Hz, 1H), 4.78 (d, J=14.9 Hz, 1H), 4.63 (d, J=14.9 Hz,1H), 4.02 (m, 1H), 3.50 (t, J=6.4 Hz, 2H), 3.09 (s, 3H), 3.00 (s, 3H),2.59 (t, J=6.4 Hz, 2H), 1.64 (d, J=6.8 Hz, 3H), 1.57 (d, J=6.7 Hz, 3H)ppm. (ES MS exact mass M+1=436.144)

EXAMPLE 146-(3-Chloro-4-fluorobenzyl)-4-hydroxy-2-isobutyl-N,N-dimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

Step 1:4-Amino-6-(3-chloro-4-fluorobenzyl)-2-isobutyl-N,N-dimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

To a solution of6-(3-chloro-4-fluorobenzyl)-3,4-dihydroxy-N,N-dimethyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide(0.5 g, 1.27 mmol) in DMSO (10 mL) was added magnesium methylate (5.48mL of a 6-10% methanol solution, 30.8 mmol), and the reaction was heatedto 60° C. for 0.5 hour. The reaction mixture was rotavapped to removeall of the MeOH. The heat gun was used to drive all MeOH from the bumpbulb. The reaction was treated with 1-iodo-2-methylpropane (0.73 mL,6.35 mmol) and allowed to stir at 60° C. for 40 minutes. LCMS showedtrace starting material remaining and mostly N-alklated product formed(O-alkylated products˜3%). The reaction was diluted with 1 mL MeOH then1 N HCl was added until a precipitate began to form. A 10 mL portion of10% sodium bisulfite was added and the brown mixture turned green. Waterwas added and the mixture stirred for 1 hr, then the liquid was decantedoff the solids. The solids were partitioned with chloroform 20 mL and 1N HCl 20 mL. The organic layer was washed 2 times more with 1 N HCl andthen with brine, dried over Na₂SO₄, filtered and evaporated to an oilthat smelled strongly of alkylating agent. The residue was diluted withtoluene and evaporated and pumped on for 4 hours. The residue would notcrystallize from ethyl acetate and methanol. The residue was passedthrough a Gilson reverse phase column eluting from 95:5 to 5:95 to givean oil after concentration. Crystallization from EtOAc:hexane affordedwhite, analytically pure product.

¹H NMR (400 MHz, DMSO) δ 13.0 (s, 1H), 7.60 (d, J=4.8 Hz, 1H), 7.40 (t,J=8.6 Hz, 1H), 7.38 (m, 1H), 4.77 (d, J=14.7 Hz, 1H), 4.58 (d, J=14.7Hz, 1H), 3.90 (dd, J=7.7, 13.2 Hz, 1H), 3.50 (m, 3H), 2.97 (s, 3H), 2.04(s, 3H), 2.54 (m, buried), 2.02 (m, 1H), 0.81 (t, J=6.22 Hz, 6H), ppm.(ES MS exact mass M+1=450.151)

EXAMPLE 14-26-(3-chloro-4-fluorobenzyl)-4-hydroxy-2-isobutyl-N-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

The title compound was prepared in accordance with the procedure setforth in Example 14, using the appropriate naphthyridine carboxamidepenultimate. MS (M+1)=436.1.

EXAMPLE 156-(3-Chloro-4-fluorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

Step 1:6-(3-Chloro-4-fluorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

To a solution of6-(3-chloro-4-fluorobenzyl)-3,4-dihydroxy-N,N-dimethyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide(0.1 g, 0.254 mmol) in dry DMSO (5 mL) was added magnesium methylate(1.097 mL of a 6-10% methanol solution, 0.792 mmol), and the reactionwas heated to 60° C. for 0.5 hour. The reaction mixture was rotavappedto remove all of the MeOH. The heat gun was used to drive all MeOH fromthe bump bulb. The reaction was treated with methyl iodide (0.079 mL,6.35 mmol) and allowed to stir at 60° C. overnight. LCMS showed tracestarting material remaining and mostly N-alklated product formed(O-alkylated products minor). The reaction was diluted with 0.5 mL MeOHthen 1 N HCl was added until a precipitate began to form. A 5 mL portionof 10% sodium bisulfite was added and the brown mixture turned green.Water was added and the mixture stirred for 1 hr, then the mixture waspartitioned with chloroform 20 mL and 1 N HCl 20 mL. The organic layerwas washed 2 times more with 1 N HCl and then with brine, dried overNa₂SO₄, filtered and evaporated to an oil. The residue was passedthrough a Gilson reverse phase column eluting from 95:5 to 5:95 to givean oil after concentration.

¹H NMR (400 MHz, CD₃OD) δ 7.5 (dd, J=2.0, 7.1 Hz, 1H), 7.34 (m, 1H),7.22 (t, J=8.8 Hz, 1H), 4.78 (d, J=14.8 Hz, 1H), 4.64 (d, J=14.8 Hz,1H), 3.52 (t, J=6.5 Hz, 2H), 3.45 (s, 3H), 3.10 (s, 3H), 2.97 (s, 3H),2.64 (t, J=6.4 Hz, 2H) ppm.

EXAMPLE 166-(4-fluorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6-tetrahydro-2,6-naphthyridine-1-carboxamide

Step 1: Ethyl6-(4-fluorobenzyl)-4-hydroxy-5-oxo-2,3,5,6-tetrahydro-2,6-naphthyridine-1-carboxamide

To solution of5-(ethoxycarbonyl)-2-(4-fluorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydro-2,6-naphthyridin-6-iumtrifluoroacetate (0.020 g, 0.045 mmol; see Example 8, Step 4) in CCl₄ (2mL) is added N-bromo succinimide (0.017 g, 0.095 mmol) and AIBN(catalytic). The reaction is heated to 80° C. for 1 hour, thenconcentrated and chromatographed on reverse phase to give the product.

Step 2:6-(4-fluorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6-tetrahydro-2,6-naphthyridine-1-carboxamide

The title compound can be prepared using a sequence of transformationssimilar to those described for Examples 9 and 10.

EXAMPLE 176-(3-chloro-4-fluorobenzyl)-N,N-diethyl-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

Step 1: Methyl6-(3-chloro-4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate

Methyl6-(3-chloro-4-fluorobenzyl)-3,4-dihydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylatewhich was prepared as described in Example 12, Steps 1-9 was convertedin a manner similar to Example 10, Step 1 for methyl6-(4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylateto obtain the title compound from preparative silica gel chromatographyeluting with 0-3% methanol in methylene chloride.

Step 2:6-(3-chloro-4-fluorobenzyl)-N,N-diethyl-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

The title compound was prepared from methyl6-(3-chloro-4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylatein a manner similar to that described in Example 12, Steps 12, 13 and14, using diethyl amine in place of dimethylamine in the stepcorresponding to Step 13 of Example 12.

¹H NMR (400 MHz, CD₃OD) δ 7.50 (dd, J=2.1, 7.1 Hz, 1H), 7.36-7.32 (m,1H), 7.23 (t, J=8.7 Hz, 1H), 4.75 (d, J=14.8 Hz, 1H), 4.67 (d, J=14.6Hz, 1H), 3.60-3.55 (m, 2H), 3.54-3.51 (m, 2H), 3.46 (s, 3H), 3.36-3.33(m, 2H), 2.68-2.61 (m, 2H), 1.25 (t, J=6.7 Hz, 3H), 1.13 (t, J=6.7 Hz,3H) ppm.

ES MS M+1=436.0

The compounds in the following table were prepared in accordance withthe procedure set forth in Example 17, using the appropriate amine inplace of the diethylamine employed in Step 2 of Example 17. When thecompound was prepared as a salt, the identity of the salt is included inparentheses following the compound name for the free base.

ES MS Example R^(G) Name (M + 1) 17-2

2-(3-chloro-4-fluorobenzyl)-8-hydroxy-6-methyl-5-[(4-methylpiperazin-4-yl)carbonyl]-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione (TFA salt) 463.0 17-3

2-(3-chloro-4-fluorobenzyl)-8-hydroxy-6-methyl-5-(thiomorpholin-4-ylcarbonyl)-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione 465.9 17-4

2-(3-chloro-4-fluorobenzyl)-8-hydroxy-6-methyl-5-(piperidin-1-ylcarbonyl)-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione 448.1 17-5

6-(3-chloro-4-fluorobenzyl)-N-(cyclopropylmethyl)-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6- naphthyridine-1-carboxamide 434.1 17-6

6-(3-chloro-4-fluorobenzyl)-N-cyclopropyl-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 420.1 17-7

6-(3-chloro-4-fluorobenzyl)-N-ethyl-4-hydroxy-N,2-dimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 422.1 17-8

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N-isopropyl-N,2-dimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 436.1 17-9

2-(3-chloro-4-fluorobenzyl)-5-[(4,4-difluoropiperidin-1-yl)carbonyl]-8-hydroxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine- 1,7-dione 484.1 17-10

2-(3-chloro-4-fluorobenzyl)-8-hydroxy-6-methyl-5-(morpholin-4-ylcarbonyl)-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione 450.1 17-11

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,2-dimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2- naphthyridine-1-carboxamide394.1 17-12

2-(3-chloro-4-fluorobenzyl)-8-hydroxy-6-methyl-5-[(4-cyclopropylpiperazin-4-yl)carbonyl]-2,3,4,6-tetrabydro-2,6- naphthyridine-1,7-dione (TFA salt)489.2

EXAMPLE 18N,N-diethyl-6-(4-fluorobenzyl)-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

Step 1: Ethyl6-(4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate

The title compound was prepared using the procedure described in Steps14 of Example 8.

Step 2: Methyl6-(4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate

The title compound was be prepared in a manner similar to that describedfor methyl6-(3-chloro-4-fluorobenzyl)-3,4-dihydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylateshown in Example 12, Steps 7, 8, 9.

Step 3: Methyl6-(4-fluorobenzyl)-3,4-dimethoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate

The title compound was prepared in the manner described in Example 10,Step 1, where the desired compound, the N-methyl O-methoxy analog, wasisolated as the second major product from the mixture of N,O- andO,O-alkylated products via silica gel chromatography eluting with 0-3%methanol in methylene chloride.

Step 4:6-(4-Fluorobenzyl)-3,4-dimethoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylicacid

The title compound was prepared in a similar manner to that described inExample 10, Step 2.

Step 5:N,N-diethyl-6-(4-fluorobenzyl)-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

The title compound was prepared in a manner similar to that described inExample 12, Steps 13 and 14.

¹HNMR (400 MHz, CD₃OD) δ 7.41-7.37 (m, 2H), 7.10-7.06 (m, 2H), 4.76 (d,J=14.6 Hz, 1H), 4.72 (d, J=14.6 Hz, 1H), 3.57 (q, J=7.14 Hz, 2H), 3.50(m, 2H), 3.45 (s, 3H), 3.37 (m, 2H)2.64 (m, 2H), 1.27-1.23 (m, 3H),1.15-1.11 (m, 3H) ppm.

ES MS M+1=402.2

The compounds in the following table were prepared in accordance withthe procedure set forth in Example 18, using the appropriate amine inplace of the diethylamine employed in Step 5 of Example 18.

ES MS Example R^(G) Name (M + 1) 18-2

N-[2-(dimethylamino)ethyl]-6-(4-fluorobenzyl)-4-hydroxy-N,2-dimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6- naphthyridine-1-carboxamide 431.3 18-3

6-(4-fluorobenzyl)-4-hydroxy-N,2-dimethyl-N-(1-methylpiperidin-4-yl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 457.3 18-4

N,6-bis(4-fluorobenzyl)-4-hydroxy-N,2-dimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 468.3

EXAMPLE 19N,N-diethyl-6-(4-fluorobenzyl)-3,4-dihydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide

The title compound was prepared using the procedure set forth above inExample 18, except that in the methylation step the O,O alkylatedproduct was isolated and used (first major product eluted off with 0-3%methanol/CH₂Cl₂).

¹H NMR (400 MHz, CD₃OD) δ 7.38 (m, 2H), 7.09 (m, 2H), 4.73 (bs, 2H),3.62 (m, 2H), 3.50 (m, 2H), 3.41 (m, 2H), 2.64 (bs, 2H), 1.22 (m, 3H),1.14 (m, 3H), ppm.

ES MS M+1=388.2

The compounds in the following table were prepared in accordance withthe procedure set forth in Example 19, using the appropriate amine inplace of the diethylamine.

ES MS Example R^(G) Name (M + 1) 19-2

6-(4-fluorobenzyl)-3,4-dihydroxy-N-isobutyl-N-methyl-5-oxo-5,6,7,8-tetrahydro-2,6- naphthyridine-1-carboxamide 402.219-3

N-ethyl-6-(4-fluorobenzyl)-3,4-dihydroxy-N-methyl-5-oxo-5,6,7,8-tetrahydro-2,6- naphthyridine-1-carboxamide 374.219-4

6-(4-fluorobenzyl)-3,4-dihydroxy-N-methyl-5-oxo-N-propyl-5,6,7,8-tetrahydro-2,6- naphthyridine-1-carboxamide 388.219-5

6-(4-fluorobenzyl)-3,4-dihydroxy-N-isopropyl-N-methyl-5-oxo-5,6,7,8-tetrahydro-2,6- naphthyridine-1-carboxamide 388.219-6

2-(4-fluorobenzyl)-7,8-dihydroxy-5-(pyrrolidin-1-ylcarbonyl)-3,4-dihydro-2,6- naphthyridin-1(2H)-one 386.219-7

2-(4-fluorobenzyl)-7,8-dihydroxy-5-(morpholin-4-ylcarbonyl)-3,4-dihydro-2,6- naphthyridin-1(2H)-one 402.2

EXAMPLE 206-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamideStep 1: Ethyl4-hydroxy-6-(4-methoxybenzyl)-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate

Ethyl4-hydroxy-6-(4-methoxybenzyl)-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylatewas prepared in a manner similar to that described in Example 8, Steps1-4 starting with 4-methoxybenzyl chloride instead of 4-fluorobenzylbromide, and also in a manner similar to that described in Example 12,Steps 1-6, starting with 4-methoxybenzyl chloride or3-chloro-4-fluorobenzyl bromide.

¹H NMR (400 MHz, CDCl₃) δ 1.39-1.42 (m, J=7.1 Hz, 3H), 3.42-3.52 (m,4H), 3.8 (s, 3H), 4.37-4.43 (q, J=7.1 Hz, 2H), 4.69 (s, 2H), 6.88-6.90(dd, J=2, 6.8 Hz, 2H), 7.24-7.26 (m, 2H), 8.42 (s, 1H), 13.05 (br s, 1H)ppm.

LRMS (M+1)=357.0

Step 2: Ethyl4-methoxy-6-(4-methoxybenzyl)-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate

The title product was prepared by treating ethyl4-hydroxy-6-(4-methoxybenzyl)-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylatewith TMS-diazomethane, using a method set forth in Step 5 of Example 8for the preparation of ethyl6-(4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate,except that after quenching with HOAc the reaction was concentrated invacuo and partitioned between sat aq NaHCO₃ and CHCl₃. LRMS (M+1)=371.0

Step 3:4-methoxy-6-(4-methoxybenzyl)-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylicacid

To a solution of ethyl4-methoxy-6-(4-methoxybenzyl)-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate(15.2 g) in THF (150 mL) was added LiOH monohydrate (5.16 g) andsufficient water to dissolve the solids. The reaction was allowed tostir at room temperature for 1.5 hours. The reaction was neutralizedwith 125 mL of 1N HCl and the THF was removed in vacuo. The resultingslurry was partitioned between CHCl₃ and 10% aqueous KHSO₄. The combinedorganics were dried over sodium sulfate, filtered, and concentrated todryness to afford the desired product as a pale tan foam. LRMS(M+1)=343.0

Step 4:4-methoxy-6-(4-methoxybenzyl)-N,N-dimethyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide

A 250 mL THF suspension of4-methoxy-6-(4-methoxybenzyl)-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylicacid (11.0 g), 8.0 g EDC, 5.7 g HOAT, and 11.2 mL TEA was stirred atroom temperature for 20 minutes, followed by addition of 45 mL of a 2MTHF solution of dimethylamine and then stirring for 1.5 hours. Thereaction was quenched with 200 mL of 1N aq HCl and stirred vigorouslyfor 30 minutes. After concentrating in vacuo until an oil formed on thewater layer, 200 mL chloroform was added. The water layer was washedagain with chloroform then the combined organic layers were washed withbrine, dried over sodium sulfate, filtered and concentrated in vacuo topure product by HPLC/MS and NMR.

HPLC/MS (M+1)=370.1

Step 5:4-methoxy-6-(4-methoxybenzyl)-N,N-dimethyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide2-oxide

A 100 ml CH₂Cl₂ solution of 12 g4-methoxy-6-(4-methoxybenzyl)-N,N-dimethyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamideand 16.8 g mCPBA (maximum 77% purity) was allowed to stir at roomtemperature until the starting material was consumed (5 hours). Thereaction was washed four times with 100 mL sat aqueous NaHCO₃ then theorganic layer was concentrated. The crude reaction was dissolved in 250mL CH₂Cl₂ and the excess mCPBA was then quenched by vigorous stirringwith a sat aq sodium sulfite solution for 30 minutes (both organic andaqueous layers were cloudy initially but then turned transparent). Thelayers were separated and the organic washed twice with sat aqueousNaHCO₃. The organic layer was dried over sodium sulfate and concentratedto pure product by HPLC/MS and NMR.

HPLC/MS (M+1)=386.2

Step 6:1-[(dimethylamino)carbonyl]-4-methoxy-6-(4-methoxybenzyl)-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridin-3-ylacetate

4-methoxy-6-(4-methoxybenzyl)-N,N-dimethyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide2-oxide (10.3 g) was dissolved in 30 ml acetic anhydride and transferredto a 50 mL heavy walled pressure flask and sealed. The reaction washeated in a 100° C. oil bath overnight. The reaction was concentrated invacuo. The remaining oil was dissolved in 5 mL EtOAc and purified on anIsco automated system affixed with a Biotage Flash 40 (L) (120 g silica)cartridge eluted with 0-10% MeOH in EtOAc over 20 minutes and hold at10% for 40 minutes. The product eluted pure by HPLC/MS and NMR.

LRMS (M+1)=428.3

Step 7:3-hydroxy-4-methoxy-6-(4-methoxybenzyl)-N,N-dimethyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide

1-[(dimethylamino)carbonyl]-4-methoxy-6-(4-methoxybenzyl)-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridin-3-ylacetate (7.55 g) was dissolved in 50 mL MeOH and treated with 6.65 mL ofa 30% by weight solution of NaOMe in MeOH at room temperature for 30minutes. The reaction was concentrated and the remaining solidpartitioned between 10% KHSO₄ and chloroform. The organic layer waswashed with brine, dried over Na₂SO₄, and then concentrated to pureproduct by HPLC/MS and NMR.

LRMS (M+1)=386.3

Step 8:4-methoxy-6-(4-methoxybenzyl)-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

To a solution of3-hydroxy-4-methoxy-6-(4-methoxybenzyl)-N,N-dimethyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide(5.00 g) in DMF (50 mL) was added magnesium methylate (14.3 mL of a6-10% methanol solution), and the reaction was heated to 50° C. for 1hour. The reaction was treated with iodomethane (17.66 mL) and allowedto stir at 50 degrees for 1.5 hours. The reaction was quenched with 15mL 10% aq KHSO₄ and concentrated in vacuo to remove the methanol. Themixture was diluted with 300 mL chloroform and the phases wereseparated. The aqueous layer was washed twice more with chloroform. Thecombined organic layers were washed with brine, dried over sodiumsulfate and concentrated in vacuo. The remaining solid was purified onan Isco automated system affixed with a Biotage Flash 40 (L) (120 g)cartridge eluted with 0-10% MeOH in EtOAc over 20 minutes and hold at10% MeOH for 45 minutes. The product eluted last, pure by HPLC/MS andNMR.

LRMS (M+1)=400.3

Step 9:4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

In a 50 mL heavy walled glass pressure flask4-methoxy-6-(4-methoxybenzyl)-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide(3.9 g) and 15 ml of (commercial) 33% HBr in HOAc were mixed. The flaskwas sealed, heated to 75° C. and allowed to stir overnight. The solventwas removed in vacuo. The remaining oil was dissolved in CH₃CN andpurified by reverse phase on a Biotage KPCM 250 compression modulecontaining a 10 cm×60 cm Kiloprep cartridge. The product elutes at 13%CH₃CN in water containing 0.1% TFA.

LRMS (M+1)=266.2.

Step 10:6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

4-Hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide(0.43 g, 0.0016 mol) was dissolved in 10 mL dry DMF and 100 mg NaH wasadded. The mixture was allowed to stir until the bubbles ceased, then3-chloro-4-fluoro benzyl bromide (0.362 g, 0.0016 mole) was added. Thereaction was quenched with 30 mL of a 10% aq KHSO₄ solution and dilutedwith 100 mL chloroform. The reaction was further diluted with 100 mLbrine and allowed to stir vigorously for 30 minutes. The layers wereseparated and the aqueous layer was washed with chloroform. The organicfractions were combined and dried over NaSO₄, filtered and concentratedunder high vacuum to remove the DMF (yield 0.5 g, 75%). HPLC analysisshowed 85% purity. The solid product was crystallized first fromisopropanol, then from ethanol.

¹H NMR (400 MHz, CDCl₃) δ 2.49-2.57 (m, 1H), 2.67-2.74 (m, 1H), 2.9 (s,3H), 3.1 (s, 3H), 3.34-3.46 (m, 1H), 3.47 (s, 1H), 3.48-3.53 (m, 1H),4.48-4.52 (d, J=15, 1H), 4.79-4.83 (d, J=15, 1H), 7.11-7.21 (m, 2H),7.34-7.36 (m, 1H), 12.94 (s, 1H).

LRMS (M+1) 408.2.

The compounds in the following table were prepared in accordance withthe procedure set forth in Example 20, using the appropriate benzylbromide in place of 3-chloro-4-fluorobenzyl bromide.

ES MS Example A B C D E Name (M + 1) 21-1 H CF₃ H H H4-hydroxy-N,N,2-trimethyl- 424.1 3,5-dioxo-6-[3-(trifluoromethyl)benzyl]- 2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 21-2 H CF₃ F H H 4-hydroxy-N,N,2-trimethyl-442.1 3,5-dioxo-6-[4-fluoro-3- (trifluoromethyl)benzyl]-2,3,5,6,7,8-hexahydro-2,6- naphthyridine-1-carboxamide 21-3 A + Btogether H H H 6-(1,3-benzodioxol-4- 400.2 formylmethyl)-4-hydroxy-N,N,2- methylenedioxy trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6- naphthyridine-1-carboxamide 21-4 H B + Ctogether H H 6-(1,3-benzodioxol-5- 400.2 form ylmethyl)-4-hydroxy-N,N,2-methylenedioxy trimethyl-3,5-dioxo- 2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 21-5 OCH₃ H H H H 4-hydroxy-6-(2- 386.2methoxybenzyl)-N,N,2- trimethyl-3,5-dioxo- 2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 21-6 H OCH₃ H H H 4-hydroxy-6-(3- 386.2methoxybenzyl)-N,N,2- trimethyl-3,5-dioxo- 2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 21-7 H CH₃ H H H 4-hydroxy-6-(3- 370.2methylbenzyl)-N,N,2- trimethyl-3,5-dioxo- 2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 21-8 H CH₃ CH₃ H H 6-(3,4-dimethylbenzyl)-4-384.2 hydroxy-N,N,2-trimethyl-3,5- dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1- carboxamide 21-9 Cl Cl H H H6-(2,3-dichlorobenzyl)-4- 424.1 hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro- 2,6-naphthyridine-1- carboxamide 21-10 F HF H H 6-(2,4-difluorobenzyl)-4- 392.1 hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro- 2,6-naphthyridine-1- carboxamide 21-11 HOCF₃ H H H 4-hydroxy-N,N,2-trimethyl- 440.1 3,5-dioxo-6-[3-(trifluoromethoxy)benzyl]- 2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 21-12 H F H H H6-(3-fluorobenzyl)-4-hydroxy- 374.2 N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6- naphthyridine-1-carboxamide 21-13 H CH₃ F H H6-(4-fluoro-3-methylbenzyl)- 388.2 4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8- hexahydro-2,6-naphthyridine- 1-carboxamide 21-14Br Cl F H H 6-(2-bromo-3-chloro-4- 485.8 fluorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo- 2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 21-16 CH₃ H H H H 4-hydroxy-6-(2- 370.2methylbenzyl)-N,N,2- trimethyl-3,5-dioxo- 2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 21-17 F H H H H6-(2-fluorobenzyl)-4-bydroxy- 374.2 N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6- naphthyridine-1-carboxamide 21-18 H H CH₃ H H4-hydroxy-6-(4- 370.2 methylbenzyl)-N,N,2- trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6- naphthyridine-1-carboxamide 21-19 H H Cl H H6-(4-chlorobenzyl)-4-hydroxy- 390.1 N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6- naphthyridine-1-carboxamide 21-20 H H OCH₃ HH 4-hydroxy-6-(4- 386.2 methoxybenzyl)-N,N,2- trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6- naphthyridine-1-carboxamide 21-21 H Cl H Cl H6-(3,5-dichlorobenzyl)-4- 424.1 hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro- 2,6-naphthyridine-1- carboxamide 21-22 H ClCl H H 6-(3,4-dichlorobenzyl)-4- 424.1 hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro- 2,6-naphthyridine-1- carboxamide 21-23 H FH F H 6-(3,5-difluorobenzyl)-4- 392.1 hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro- 2,6-naphthyridine-1- carboxamide 21-24 HOCH₃ H OCH₃ H 6-(3,5-dimethoxybenzyl)-4- 416.2hydroxy-N,N,2-trimethyl-3,5- dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1- carboxamide 21-25 H Cl CH₃ H H6-(3-chloro-4-methylbenzyl)- 404.1 4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8- hexahydro-2,6-naphthyridine- 1-carboxamide 21-26H F CH₃ H H 6-(3-fluoro-4-methylbenzyl)- 388.24-hydroxy-N,N,2-trimethyl- 3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine- 1-carboxamide 21-27 F H H F H6-(2,5-difluorobenzyl)-4- 392.1 hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro- 2,6-naphthyridine-1- carboxamide 21-28 F ClH H H 6-(3-chloro-2-fluorobenzyl)-4- 408.1 hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro- 2,6-naphthyridine-1- carboxamide 21-29 F HCl H H 6-(4-chloro-2-fluorobenzyl)-4- 408.1 hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro- 2,6-naphthyridine-1- carboxamide 21-30 F HH Cl H 6-(5-chloro-2-fluorobenzyl)-4- 408.1 hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro- 2,6-naphthyridine-1- carboxamide 21-31 FCH₃ H H H 6-(2-fluoro-3-methylbenzyl)- 388.2 4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8- hexahydro-2,6-naphthyridine- 1-carboxamide 21-32CH₃ H H F H 6-(5-fluoro-2-methylbenzyl)- 388.24-hydroxy-N,N,2-trimethyl- 3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine- 1-carboxamide 21-33 H CH₃ H CH₃ H6-(3,5-dimethylbenzyl)-4- 384.3 hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro- 2,6-naphthyridine-1- carboxamide 21-34 H HOH H H 4-hydroxy-6-(4- 372.2 hydroxybenzyl)-N,N,2- trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6- naphthyridine-1-carboxamide 21-35 H B + Ctogether H H 6-(2,3-dihydro-1,4- 414.2 form benzodioxin-6-ylmethyl)-4-ethylenedioxy hydroxy-N,N,2-trimethyl-3,5- dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1- carboxamide 21-36 H OCH₃ F H H6-(4-fluoro-3-methoxybenzyl)- 404.2 4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8- hexahydro-2,6-naphthyridine- 1-carboxamide 21-37H Cl OCH₃ H H 6-(3-chloro-4- 420.1 methoxybenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo- 2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 21-38 H CH₃ Cl H H6-(4-chloro-3-methylbenzyl)- 404.1 4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8- hexahydro-2,6-naphthyridine- 1-carboxamide 21-39H F F H H 6-(3,4-difluorobenzyl)-4- 392.4 hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro- 2,6-naphthyridine-1- carboxamide 21-40 Cl HF H H 6-(2-chloro-4-fluorobenzyl)-4- 408.0 hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro- 2,6-naphthyridine-1- carboxamide 21-41 H ClH H H 6-(3-chlorobenzyl)-4-hydroxy- 390.0 N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6- naphthyridine-1-carboxamide

EXAMPLE 228-hydroxy-2-(4-methoxybenzyl)-6-methyl-5-(pyrrolidin-1-ylcarbonyl)-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione

The title compound was prepared using a procedure similar to that setforth above in Example 20, Steps 1 to 4, except that the N-oxidation,rearrangement and alkyation steps were done before the amide was formed,and wherein pyrrolidine was employed instead of dimethylamine. LCMS(M+1)=412.2

EXAMPLE 234-hydroxy-6-(4-methoxybenzyl)-N,2-dimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

The title compound was prepared was prepared in a manner similar to thatdescribed for Example 22, wherein methylamine was employed in place ofpyrrolidine. LCMS (M+1)=372.2

EXAMPLE 24 Methyl6-(1,3-benzodioxol-5-ylmethyl)-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate

The title compound was prepared from methyl4-hydroxy-6-(4-methoxybenzyl)-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate,which was prepared in a manner similar to that described for Example 20,step 8, except that under longer reaction time the O-methyl group islost. This intermediate was treated as described for Example 20, steps 9and 10 to give the title compound. LCMS (M+1)=387.1

EXAMPLE 256-(3-Chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(4-methylphenyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

Step 1: Ethyl6-(3-chloro-4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate

A mixture of ethyl6-(3-chloro-4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate(1.00 g, 2.64 mmol; Example 12, step 6), cesium carbonate (1.12 g, 3.43mmol), methyl iodide (0.41 g, 2.90 mmol) in DMF (30 mL) was stirred atroom temperature overnight. The reaction mixture was filtered and thefiltrate concentrated under vacuum. The residue was partitioned betweenethyl acetate and brine. The organic extract was dried over anhydroussodium sulfate, filtered and concentrated under vacuum to provide thetitled ester.

¹H NMR (400 MHz, CDCl₃) δ 8.48 (s, 1H), 7.41 (dd, J=6.9, 2.2 Hz, 1H),7.21-7.26 (m, 1H), 7.11 (t, J=8.6 Hz, 1H), 4.70 (s, 2H), 4.43 (q, J=7.2Hz, 2H), 4.12 (s, 3H), 3.46 (t, J=6.4 Hz, 2H), 3.32 (t, J=6.4 Hz, 2H),1.43 (t, J=7.1 Hz, 3H). (ES MS M+1=393.01)

Step 2:6-(3-Chloro-4-fluorobenzyl)-4-methoxy-N,N-dimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

In a manner similar to that described for6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide(Example 13, steps 1 to 5), the title compound was prepared.

¹H NMR (400 MHz, CDCl₃₁) 7.38 (dd, J=6.9, 2.0 Hz, 1H), 7.19-7.24 (m,1H), 7.11 (t, J=8.6 Hz, 1H), 4.67 (s, 2H), 4.11 (s, 3H), 3.38-3.44 (m,3H), 3.06 (br s, 3H), 2.96 (br s, 3H), 2.58 (t, J=6.0 Hz, 2H).

(ES MS M+1=408.05)

Step 3:6-(3-Chloro-4-fluorobenzyl)-4-methoxy-N,N-dimethyl-2-(4-methyl-phenyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

A mixture of6-(3-chloro-4-fluorobenzyl)-4-methoxy-N,N-dimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide(0.10 g, 0.25 mmol), p-tolylboronic acid (0.13 g, 0.98 mmol), copper(II) acetate (67 mg, 0.37 mmol), activated molecular sieves type 4A (1g), and pyridine (40 mg, 0.50 mmol) in dichloromethane (12 mL) wasstirred at room temperature overnight. The reaction mixture was treatedwith a mixture of aqueous NH₄OH (1 mL, 1M) and methanol (3 mL). Afterstirring at room temperature for 15 minutes, the slurry was filtered,and the filtrate concentrated under vacuum. The residue was subjected tocolumn chromatography on silica gel eluting with a gradient of 0 to 15%of methanol in chloroform. Collection and concentration of appropriatefractions provided the title compound.

¹HNMR (400 MHz, CDCl₃) δ 7.40 (dd, J=6.9, 2.0 Hz, 1H), 7.20-7.30 (m,4H), 7.06-7.14 (m, 2H), 4.86 (d, J=14.8 Hz, 1H), 4.52 (d, J=14.8 Hz,1H), 4.14 (s, 3H), 3.48-3.55 (m, 1H), 3.31-3.39 (m, 1H), 2.81 (s, 3H),2.66 (s, 3H), 2.61-2.69 (m, 1H), 2.38-2.47 (m, 1H), 2.38 (s, 3H). (ES MSM+1=498.03)

Step 4:6-(3-Chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(4-methyl-phenyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

A solution of6-(3-chloro-4-fluorobenzyl)-4-methoxy-N,N-dimethyl-2-(4-methyl-phenyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide(0.054 g, 0.108 mmol) in anhydrous dichloromethane (10 mL) was treatedwith a solution of boron tribromide (0.3 mL, 1M) in dichloromethane. Thereaction mixture was stirred at room temperature for 3 hours. Theproduct mixture was concentrated under vacuum, and the residue subjectto preparative reverse phase HPLC purification. Collection andlyophilization of appropriate fractions provide the titled compound.

¹HNMR (400 MHz, DMSO-d₆) δ 13.20 (br s, 1H), 7.60 (dd, J=6.9, 1.8 Hz,1H), 7.37-7.45 (m, 2H), 7.04-7.28 (m, 4H), 4.81 (d, J=14.9 Hz, 1H), 4.62(d, J=14.9 Hz, 1H), 3.48-3.60 (m, 2H), 2.83 (s, 3H), 2.55-2.59 (m, 2H),2.54 (s, 3H), 2.34 (s, 3H). (ES MS M+1=483.99)

The compounds in the following table were prepared in accordance withthe procedure set forth in Example 25, using the appropriate boronicacid in place of p-tolylboronic acid.

ES MS Example R^(G) Name (M + 1) 26

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-phenyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 470 27

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(3-thienyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 476 28

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-pyridin-3-yl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 471 29

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-{4-[methoxycarbonyl]-phenyl}-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1- carboxamide 528 30

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-[4-(amino)carbonyl-phenyl]-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1- carboxamide 513 31

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-{4-[(methylamino)carbonyl]-phenyl}-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6- naphthyridine-1-carboxamide 527 32

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-{4-[(ethylamino)carbonyl]-phenyl}-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6- naphthyridine-1-carboxamide 541 33

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-{4-[(isopropylamino)carbonyl]-phenyl}-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6- naphthyridine-1-carboxamide555 34

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-{4-[(dimethylamino)carbonyl]-phenyl}-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6- naphthyridine-1-carboxamide541 35

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-{4-[(diethylamino)carbonyl]-phenyl}-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6- naphthyridine-1-carboxamide 569 36

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-{3-[(dimethylamino)carbonyl]-phenyl}-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6- naphthyridine-1-carboxamide541 37

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(4-nitrophenyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 515 38

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-[4-(acetylamino)phenyl]-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1- carboxamide 527 39

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-[4-(acetylmethylamino)phenyl]-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1- carboxamide 541 40

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-[4-methyl(trifluoroacetyl)-aminophenyl]-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 595 41

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-{4-[(methylaminocarbonyl)-methylamino]phenyl}-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 556 42

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-{4-[(dimethylaminocarbonyl)-methylamino]phenyl}-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 570 43

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-{4-[(methoxycarbonyl)-amino]phenyl}-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6- naphthyridine-1-carboxamide 543 44

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-{4-[(methoxycarbonyl)methyl-amino]phenyl}-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 557 45

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-{4-[(methylsulfonyl)-amino]phenyl}-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6- naphthyridine-1-carboxamide 563 46

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N- dimethyl-2-{4-[methyl(methyl-sulfonyl)amino]phenyl}-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 577 47

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-[4-(aminosulfonyl)phenyl]-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1- carboxamide 549 48

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-[4-(methylaminosulfonyl)-phenyl]-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1- carboxamide 563 49

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-[4-(morpholin-4-ylsulfonyl)-phenyl]-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6- naphthyridine-1-carboxamide 619 50

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-[4-(methylsulfonyl)-phenyl]-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1- carboxamide 548 51

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(3-cyanophenyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 495 52

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(4-cyanophenyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 495 53

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(4-acetylphenyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 512

EXAMPLE 546-(3-Chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(cyanomethyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

The title compound was prepared in a manner similar to that describedfor6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide(Example 13, step 6), wherein bromoacetonitrile was employed in place of2-iodopropane.

¹H NMR (400 MHz, CD₃OD) δ 7.51 (dd, J=2.2, 6.9 Hz, 1H), 7.37-7.33 (m,1H), 7.23 (t, J=9.0 Hz, 1H), 5.06 (d, J=17.6 Hz, 1H), 4.83 (d, J=17.6Hz, 1H), 4.78 (d, J=15.0 Hz, 1H), 4.64 (d, J=15.0 Hz, 1H), 3.54 (t,J=6.4 Hz, 2H), 3.12 (s, 3H), 3.03 (s, 3H), 2.72-2.61 (m, 2H). (ES MSM+1=433)

The compounds in the following table were prepared in accordance withthe procedure n Example 54, using the appropriate halide reagent inplace of bromoacetonitrile.

ES MS Example R^(G) (halide reagent) Name (M + 1) 55

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(1-cyanoethyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 447 56

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(2-amino-2-oxoethyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1- carboxamide 451 57

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(2-amino-1-methyl-2-oxoethyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1- carboxamide 465 58

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(cyclopropylmethyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1- carboxamide 448 59

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(cyclobutylmethyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1- carboxamide 462 60

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(cyclohexylmethyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1- carboxamide 490 61

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(2-methoxyethyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1- carboxamide 452 62

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(2,2,2-trifluoroethyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1- carboxamide 476 63

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-benzyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 484 64

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(4-fluorobenzyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 502 65

6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(3-chloro-4-fluorobenzyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1- carboxamide 536

EXAMPLE 666-(3-Chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(2-pyrrolidin-1-ylethyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

A mixture of6-(3-chloro-4-fluorobenzyl)-3,4-dihydroxy-N,N-dimethyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide(0.075 g, 0.19 mmol; Example 13, step 5) and magnesium methoxide inmethanol (0.06 mL, 6-10% methanol solution available from Aldrich) inDMSO (2 mL) was heated at 60° C. for 30 minutes. Methanol wasexhaustively removed under vacuum over 45 minutes. The residual DMSOsolution was treated with 1-bromo-2-chloroethane (0.136 g, 0.95 mmol)and stirred at 60° C. under an atmosphere of nitrogen overnight. Theproduct mixture was treated with pyrrolidine (0.27 g, 3.8 mmol) andsodium iodide (0.14 g, 0.95 mmol) and heated at 60° C. overnight. Thereaction was partitioned between methylene chloride and aqueous sodiumbisulfate. The organic extract was dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum. The residue was subjected topreparative HPLC purification on C-18 reverse stationary phase columneluting with a gradient of water—acetonitrile in the presence of 0.1%trifluoroacetic acid. Collection and lyophilization of appropriatefractions provided the titled compound.

¹H NMR (400 MHz, CD₃OD) δ 7.50 (dd, J=1.9, 7.2 Hz, 1H), 7.32 (m, 1H),7.22 (t, J=8.8 Hz, 1H), 4.80-4.70 (m), 4.52 (d, J=14.6 Hz, 1H),3.97-3.67 (m), 3.54 (t, J=6.3 Hz, 2H), 3.13 (s, 3H), 3.01 (s, 3H), 2.65(t, J=6.3 Hz, 2H), 2.2-2.0 (m). (ES MS exact mass M+1=491.1863)

EXAMPLE 676-(3-Chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(2-morpholin-4-ylethyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

The title compound was prepared in a manner similar to that describedfor6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(2-pyrrolidin-1-ylethyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide(Example 66), substituting pyrrolidine with morpholine. (ES MS M+1=507)

EXAMPLE 686-(3-Chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(2-aminoethyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

The title compound was prepared in a manner similar to that describedfor6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(2-pyrrolidin-1-ylethyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide(Example 66), substituting 1-bromo-2-chloroethane with1-bromo-2-N-Boc-aminoethane. The alkylation product mixture waspartitioned between chloroform and aqueous sodium bisulfite. The organicextract was washed with brine, dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum. The residue was subjected topreparative HPLC purification on C-18 reverse stationary phase columneluting with a gradient of water—acetonitrile in the presence of 0.1%trifluoroacetic acid. Collection and lyophilization of appropriatefractions provided the N-Boc aminoethylated intermediate. A cold (0° C.)solution of the above N-Boc amino intermediate (36 mg, 0.07 mmol) indioxane (2 mL) was treated with a solution of anhydrous HCl in dioxane(0.17 mL, 4M). The reaction mixture was stirred at 0° C. for 1 hour andconcentrated under vacuum. The residue was triturated with anhydrousdiethyl ether to provide the title compound as hydrogen chloride salt.

¹H NMR (400 MHz, CD₃OD) δ 7.50 (dd, J=1.9, 7.2 Hz, 1H), 7.32 (m, 1H),7.24 (t, J=8.4 Hz, 1H), 4.90-4.80 (m), 4.68 (d, J=14.1 Hz, 1H), 3.6-2.5(m), 3.31 (s, 6H). (ES MS exact mass M+1=437.1391)

EXAMPLE 696-(4-Fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-isopropyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

A mixture of6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-isopropyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide(95 mg, 0.22 mmol; Example 13) and 10% palladium on charcoal (0.11 g) inmethanol (5 mL) was stirred under a balloon of hydrogen gas at roomtemperature overnight. The reaction mixture was filtered, and thefiltrate concentrated under vacuum. The residue was subjected topreparative HPLC purification on C-18 reverse stationary phase columneluting with a gradient of water—acetonitrile in the presence of 0.1%trifluoroacetic acid. Collection and lyophilization of appropriatefractions provided the titled compound.

¹H NMR (400 MHz, CD₃OD) δ 7.37 (dd, J=5.5, 8.6 Hz, 2H), 7.08 (t, J=8.6Hz, 2H), 4.77 (d, J=14.7 Hz, 1H), 4.66 (d, J=14.7 Hz, 1H), 4.03 (m, 1H),3.48 (t, J=6.4 Hz, 2H), 3.09 (s, 3H), 3.00 (s, 3H), 2.57 (t, J=6.4 Hz,2H), 1.64 (d, J=6.8 Hz, 3H), 1.57 (d, J=6.6 Hz, 3H). (ES MS exact massM+1=402.1853)

EXAMPLE 706-(4-Fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-isobutyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

The title compound was prepared in a manner similar to that describedfor6-(4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-isopropyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide(Example 69), using6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-isobutyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide(Example 14). (ES MS M+1=416)

EXAMPLE 716-(5-Chloro-4-fluoro-2-iodobenzyl)-4-hydroxy-N,N-dimethyl-2-isopropyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

A mixture of6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-isopropyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide(43 mg, 0.10 mmol; Example 13) and N-iodosuccinamide (22 mg, 0.1 mmol)in trifluoromethanesulfonic acid at 0° C. was stirred for 10 minutes.The mixture was diluted with methanol and subjected to preparative HPLCpurification on C-18 reverse stationary phase column eluting with agradient of water—acetonitrile in the presence of 0.1% trifluoroaceticacid. Collection and lyophilization of appropriate fractions providedthe titled compound.

¹H NMR (400 MHz, CD₃OD) δ 7.82 (d, J=8.4 Hz, 1H), 7.42 (d, J=7.3 Hz,1H), 4.79 (d, J=15.6 Hz, 1H), 4.70 (d, J=15.6 Hz, 1H), 4.05 (m, 1H),3.52 (t, J=6.4 Hz, 2H), 3.10 (s, 3H), 3.03 (s, 3H), 2.64 (t, J=6.4 Hz,2H), 1.65 (d, J=6.8 Hz, 3H), 1.59 (d, J=6.6 Hz, 3H). (ES MS exact massM+1=562.0383)

EXAMPLE 726-(5-Chloro-4-Fluoro-2-iodobenzyl)-4-hydroxy-N,N-dimethyl-2-isobutyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

The title compound was prepared in a manner similar to that describedfor6-(4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-isopropyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide(Example 71), using6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-isobutyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide(Example 14). (ES MS M+1=576)

EXAMPLE 73N-[6-(3-Chloro-4-fluorobenzyl)-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]-N-methylmethanesulfonamide

Step 1:tert-Butyl-[6-(3-chloro-4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]carbamate

A solution of ethyl6-(3-chloro-4-fluorobenzyl)-4-methoxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylicacid (1.2 g, 3.04 mmol; Example 12, step 12), diisopropylethylamine(0.37 g, 3.65 mmol), and diphenylphosphoryl azide (1.00 g, 3.65 mmol) ina 1:1 mixture of dioxane and tert-butanol (30 mL) was heated in an oilbath 90° C. for 3 hours. The reaction mixture was concentrated undervacuum. The residue was subjected to column chromatography on silica geleluting with 5% methanol in dichloromethane. Collection andconcentration of appropriate fractions provided the titled compound.

¹HNMR (400 MHz, CDCl₃) δ 7.34 (dd, J=6.8, 2.0 Hz, 1H), 7.21-7.17 (m,1H), 7.09 (t, J=8.8 Hz, 1H), 6.06 (br s, 1H), 4.64 (s, 2H), 4.06 (s,3H), 3.53 (s, 3H), 3.34 (t, J=6.1 Hz, 2H), 2.55 (t, J=6.1 Hz, 2H), 1.45(9H, s).

Step 2:N-[6-(3-Chloro-4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]methanesulfonamide

A mixture oftert-butyl-[6-(3-chloro-4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]carbamate(0.49 g, 1.07 mol) and sodium hydride (54 mg, 1.34 mmol; 60% dispersionin oil) in anhydrous DMF (6 mL) was stirred at 0° C. for 30 minutes.Methanesulfonyl chloride (0.18 g, 1.61 mmol) was added, and the mixturewas allowed to warm up slowly to room temperature. The reaction mixturewas quenched with aqueous acid and diluted with dichloromethane. Theorganic extract was washed with brine, dried over anhydrous sodiumsulfate, filtered, and concentrated under vacuum. The residue wassubjected to column chromatograph on silica gel eluting with a mixtureof 1% methanol in dichloromethane. Collection and concentration ofappropriate fractions provided the intermediatetert-butyl-[6-(3-chloro-4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl](methylsulfonyl)carbamate(ES MS M+1=544). A solution of the above intermediate sulfonylcarbamate(281 mg, 0.52 mmol) and trifluoroacetic acid (5 mL) in anhydrousdichloromethane (5 mL) was stirred at room temperature for 10 minutes.The product mixture was concentrated under vacuum. The residue waspartitioned between dichloromethane and aqueous acid. The organicextract was washed dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum to provide the title compound. ES MS M+1=444

Step 3:N-[6-(3-Chloro-4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]-N-methylmethane-sulfonamide

A cold (0° C.) solution ofN-[6-(3-chloro-4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]methanesulfonamide(60 mg, 0.14 mmol) in anhydrous DMF (1 mL) was treated with sodiumhydride (6.8 mg, 0.17 mmol; 60% dispersion in oil). The resultantmixture was stirred at the same temperature for 30 minutes, and treatedwith iodomethane (38 mg, 0.27 mmol). The reaction mixture was allowed toslowly warmed up to room temperature. The product mixture wasconcentrated under vacuum. The residue was partitioned betweenchloroform and brine. The organic extract was dried over anhydroussodium sulfate, filtered, and concentrated under vacuum to provide thetitle compound. ES MS M+1=458

Step 4:N-[6-(3-Chloro-4-fluorobenzyl)-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]-N-methylmethane-sulfonamide

A solution ofN-[6-(3-chloro-4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]-N-methylmethane-sulfonamide(48 mg, 0.11 mmol) in 33% HBr in acetic acid (1 mL) was heated in an oilbath at 50° C. for 15 minutes. The product mixture was concentratedunder vacuum, and the residue subject to preparative reverse phase HPLCpurification. Collection and lyophilization of appropriate fractionsafforded an oil. Trituration of the residual oil with diethyl etherprovided the title compound as off white solid.

¹HNMR (400 MHz, CDCl₃) δ 7.36 (dd, J=1.8, 6.8 Hz, 1H), 7.20 (m, 1H),7.14 (t, J=8.6 Hz, 1H), 4.68 (d, J=14.6 Hz, 1H), 4.63 (d, J=14.6 Hz,1H), 3.58 (s, 3H), 3.48 (m, 2H), 3.18 (s, 6H), 3.10 (s, 3H), 2.92 (m,1H), 2.74 (m, 1H). (ES MS M+1=444.0797)

The compounds in the following table were prepared in accordance withthe procedure set forth in Example 73.

ES MS Example R^(G) R^(H) Name (M + 1) 74

CH₃ N-[6-(3-chloro-4-fluorobenzyl)-4- hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6- naphthyridin-1-yl]-N- methylethanesulfonamide458 75

isobutyl N-[6-(3-chloro-4-fluorobenzyl)-4- hydroxy-2-isobutyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6- naphthyridin-1-yl]-N-methylmethanesulfonamide 486 76

isobutyl N-[6-(3-chloro-4-fluorobenzyl)-4- hydroxy-2-isobutyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6- naphthyridin-1-yl]-N- ethylmethanesulfonamide500

EXAMPLE 77N-[6-(3-Chloro-4-fluorobenzyl)-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]-N,N′,N′-trimethylurea

In a manner similar to that described forN-[6-(3-chloro-4-fluorobenzyl)-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]-N-methylmethanesulfonamide(Example 73), substituting methanesulfonyl chloride withN,N-dimethylcarbamoyl chloride in step 2, the title compound wasprepared.

¹HNMR (400 MHz, CDCl₃) δ 7.34 (dd, J=6.8, 2.0 Hz, 1H), 7.21-7.17 (m,1H), 7.09 (t, J=8.8 Hz, 1H), 4.69 (s, 2H), 3.56 (s, 3H), 2.98 (s, 3H),2.67 (s, 3H). ES MS M+1=437.

EXAMPLE 782-(3-Chloro-4-fluorobenzyl)-8-hydroxy-6-methyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione

Step 1:N′-Acetyl-6-(3-Chloro-4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carbohydrazide

A suspension of6-(3-chloro-4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylicacid (0.20 g, 0.51 mmol; Example 12, step 12) in anhydrousdichloromethane (5 mL) and anhydrous DMF (0.05 mL) at room temperaturewas treated with oxalyl chloride (0.09 mL, 1.01 mmol). The reactionmixture was stirred at room temperature for 3 hours and concentratedunder vacuum. The residue was redissolved in anhydrous dichloromethane(5 mL), cooled to 0° C., and treated with a mixture of acetylhydrazide(56 mg, 0.76 mmol), triethylamine (0.26 g, 2.53 mmol), and DMAP(catalytic amount). The product mixture was stirred at room temperatureovernight, diluted with dichloromethane and washed with water. Theorganic extract was dried over anhydrous sodium sulfate, filtered,concentrated under vacuum. The residue was subjected to columnchromatography on silica gel eluting with 5% methanol indichloromethane. Collection and concentration of appropriate fractionsprovided the titled compound. ES MS M+1=451

Step 2:2-(3-Chloro-4-fluorobenzyl)-8-hydroxy-6-methyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione

A mixture ofN′-acetyl-6-(3-chloro-4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carbohydrazide(55 mg, 0.12 mmol) and Burgess reagent (116 mg, 0.49 mmol) in anhydrousTHF (2 mL) was heated in a microwave oven at 120° C. for 15 minutes. Thereaction mixture was concentrated under vacuum. The residue wassubjected to column chromatography on silica gel eluting with 5%methanol in dichloromethane. Collection and concentration of appropriatefractions provided the intermediate oxazole. A solution of thisintermediate (31 mg, 0.07 mmol) in 33% HBr in acetic acid (2 mL) wasstirred at room temperature for 1 hour. The product mixture wasconcentrated under vacuum. The residue was partitioned between water anddichloromethane. The organic extract was dried over anhydrous magnesiumsulfate, filtered, and concentrated under vacuum. The residue wastriturated with anhydrous diethyl ether to provide the titled compound.

¹HNMR (400 MHz, CDCl₃) δ 7.33 (dd, J=6.8, 2.0 Hz, 1H), 7.21-7.17 (m,1H), 7.11 (t, J=8.6 Hz, 1H), 4.66 (s, 2H), 3.42 (s, 3H), 3.40 (t, J=6.1Hz, 2H), 2.72 (t, J=6.1 Hz, 2H), 2.63 (s, 3H). ES MS M+1=419

EXAMPLE 795-Bromo-2-(3-chloro-4-fluorobenzyl)-8-hydroxy-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione

Step 1:5-Bromo-2-(3-chloro-4-fluorobenzyl)-8-methoxy-3,4-dihydro-2,6-naphthyridin-1(2H)-one

A suspension of6-(3-chloro-4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylicacid (3.5 g, 9.59 mmol; Example 12, step 12) in anhydrousdichloromethane (60 mL) and anhydrous DMF (0.45 mL) at room temperaturewas treated with oxalyl chloride (1.7 mL, 19.2 mmol). The reactionmixture was stirred at room temperature for 2 hours and concentratedunder vacuum. A solution of the residue and AIBN (0.47 g, 2.88 mmol) inanhydrous dichloromethane (30 mL) was added portionwise to a solution of2-pyridinethiol-N-oxide (2.4 g, 19.2 mmol) in a mixture ofbromotrichloromethane (90 mL) and dichloroethane (30 mL) at 100° C. overa period of 20 minutes (Barton et al, Tetrahedron Lett., 5939, 1985).The mixture was heated at the same temperature for 20 minutes, cooled toroom temperature, and concentrated under vacuum. The residue wassubjected to column chromatography on silica gel eluting with 2%methanol in dichloromethane. Collection and concentration of appropriatefractions provided the titled compound.

¹HNMR (400 MHz, CDCl₃) δ 8.14 (s, 1H), 7.38 (dd, J=6.9, 2.0 Hz, 1H),7.22-7.19 (m, 1H), 7.10 (t, J=8.6 Hz, 1H), 4.66 (s, 2H), 4.03 (s, 3H),3.48 (t, J=6.4 Hz, 2H), 2.94 (t, J=6.4 Hz, 2H). ES MS M+1=399, 401, 403.

Step 2:5-Bromo-2-(3-chloro-4-fluorobenzyl)-8-methoxy-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione

5-Bromo-2-(3-chloro-4-fluorobenzyl)-8-methoxy-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dionewas prepared in a manner similar to that described in Example 12, step 7to 9, except the oxidation of5-bromo-2-(3-chloro-4-fluorobenzyl)-8-methoxy-3,4-dihydro-2,6-naphthyridin-1(2H)-oneto the corresponding pyridine N-oxide was oxidized with hydrogenperoxide urea complex (Caron et al., Tetrahedron Lett., 2299, 2000).

¹HNMR (400 MHz, CDCl₃) δ 7.37 (dd, J=7.0, 2.0 Hz, 1H), 7.25-7.18 (m,1H), 7.10 (t, J=8.6 Hz, 1H), 4.68 (s, 2H), 4.05 (s, 3H), 3.44 (t, J=6.2Hz, 2H), 2.81 (t, J=6.2 Hz, 2H).

Step 3:5-Bromo-2-(3-chloro-4-fluorobenzyl)-8-hydroxy-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione

A solution of5-bromo-2-(3-chloro-4-fluorobenzyl)-8-methoxy-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione(1.40 g, 3.37 mmol) in 33% HBr in acetic acid (20 mL) was stirred atroom temperature for 1 hour. The product mixture was concentrated undervacuum. The residue was dissolved in methanol, concentrated undervacuum, and triturated with anhydrous diethyl ether. The solidprecipitated was filtered to provide the titled compound.

¹HNMR (400 MHz, CDCl₃) δ 9.03 (br s, 1H), 7.35 (dd, J=6.8, 2.0 Hz, 1H),7.21-7.17 (m, 1H), 7.13 (t, J=8.6 Hz, 1H), 4.66 (s, 2H), 3.49 (t, J=6.2Hz, 2H), 2.84 (t, J=6.2 Hz, 2H).

EXAMPLE 805-Bromo-2-(3-chloro-4-fluorobenzyl)-8-hydroxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione

N-Methylation of5-bromo-2-(3-chloro-4-fluorobenzyl)-8-hydroxy-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione(Example 79) was carried out as described in Example 12, step 10. Theresultant reaction mixture was cooled to 0° C. and acidified withaqueous HCl. The resultant mixture was filtered and washed with diethylether to provide the titled compound as creamy white solid.

¹HNMR (400 MHz, CDCl₃) δ 7.34 (dd, J=7.0, 2.0 Hz, 1H), 7.24-7.18 (m,1H), 7.14 (t, J=8.6 Hz, 1H), 4.65 (s, 2H), 3.77 (s, 3H), 3.44 (t, J=6.2Hz, 2H), 2.84 (t, J=6.2 Hz, 2H).

EXAMPLE 812-(3-Chloro-4-fluorobenzyl)-8-hydroxy-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione

Step 1:6-(3-Chloro-4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylicacid

A solution of ethyl3,4-bis(acetyloxy)-6-(3-chloro-4-fluorobenzyl)-5-oxo-5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate(1.00 g, 2.09 mmol; Example 12, step 8) and lithium hydroxide (0.70 g,16.70 mmol) in a mixture of THF-methanol-water (30 mL, 1:1:1 by volume)was heated under reflux in an oil bath at 90° C. overnight. The productmixture was acidified and concentrated under vacuum. The residue wastriturated with diethyl ether. The solid precipitated was filtered andwashed with ether to provide the titled compound. ES MS M+1=367.

Step 2:2-(3-Chloro-4-fluorobenzyl)-8-hydroxy-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione

A mixture of6-(3-chloro-4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylicacid (0.30 g, 0.82 mmol) and quinoline (0.11 g, 0.82 mmol) was heated at190° C. for 2.5 hours. The product mixture was cooled to roomtemperature and triturated with diethyl ether. The solid precipitatedwas filtered, and was subjected to preparative reverse phase HPLCpurification. Collection and lyophilization of appropriate fractionsprovide the titled compound.

¹HNMR (400 MHz, CD₃OD) δ 7.49 (dd, J=6.8, 2.0 Hz, 1H), 7.36-7.32 (m,1H), 7.22 (t, J=8.8 Hz, 1H), 6.66 (br s, 1H), 4.67 (s, 2H), 3.51 (t,J=6.1 Hz, 2H), 2.74 (t, J=6.1 Hz, 2H). ES MS M+1=323

EXAMPLE 822-(3-Chloro-4-fluorobenzyl)-8-hydroxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione

Step 1:2-(3-Chloro-4-fluorobenzyl)-8-methoxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione

A solution of2-(3-chloro-4-fluorobenzyl)-8-hydroxy-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione(0.40 g, 1.24 mmol; Example 81), methyl iodide (1.76 g, 12.4 mmol), andcesium carbonate (2.02 g, 6.20 mmol) in THF (50 mL) was heated underreflux overnight. The product mixture concentrated under vacuum. Theresidue was partitioned between water and ethyl acetate. The organicextract was dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residual oil was subjected to preparativereverse phase HPLC purification. Collection and lyophilization ofappropriate fractions provide the titled compound.

¹HNMR (400 MHz, CDCl₃) δ 7.37 (dd, J=6.8, 2.0 Hz, 1H), 7.25-7.21 (m,1H), 7.12 (t, J=8.8 Hz, 1H), 6.92 (s, 1H), 4.69 (s, 2H), 4.09 (s, 3H),3.57 (s, 3H), 3.40 (t, J=6.1 Hz, 2H), 2.62 (t, J=6.1 Hz, 2H). ES MSM+1=351

Step 2:2-(3-Chloro-4-fluorobenzyl)-8-hydroxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione

A solution of2-(3-chloro-4-fluorobenzyl)-8-methoxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione(30 mg, 0.086 mmol) and 33% HBr in acetic acid (5 mL) in acetic acid (10mL) was stirred at room temperature for 2 hours. The product mixture wasconcentrated under vacuum. The residue was subjected to preparativereverse phase HPLC purification. Collection and lyophilization ofappropriate fractions provide the titled compound.

ES MS M+1=337

EXAMPLE 832-(3-Chloro-4-fluorobenzyl)-5-ethyl-8-hydroxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione

Step 1:5-Bromo-2-(3-chloro-4-fluorobenzyl)-8-methoxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione

A solution of5-bromo-2-(3-chloro-4-fluorobenzyl)-8-hydroxy-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione(8.00 g, 19.92 mmol; Example 79), methyl iodide (28.27 g, 199.19 mmol),and cesium carbonate (32.45 g, 99.59 mmol) in THF (100 mL) was heatedunder reflux overnight. The product mixture concentrated under vacuum.The residue was partitioned between water and ethyl acetate. The organicextract was dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residual oil was subjected to preparativereverse phase HPLC purification. Collection and lyophilization ofappropriate fractions provide the titled compound.

ES MS M+1=429.

Step 2:2-(3-Chloro-4-fluorobenzyl)-5-ethyl-8-methoxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione

A solution of5-bromo-2-(3-chloro-4-fluorobenzyl)-8-methoxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione(0.40 g, 0.93 mmol), tri-n-butyl vinyl tin (0.38 g, 1.21 mmol), andbis(tri-phenylphosphine)palladium (II) chloride (65 mg, 0.093 mmol) inTHF (30 mL) was heated under reflux for two hours. The product mixtureconcentrated under vacuum. The residue was subjected to preparativereverse phase HPLC purification. Collection and lyophilization ofappropriate fractions provide the intermediate vinyl intermediate. ES MSM+1=377. A mixture of this vinyl intermediate (60 mg, 0.16 mmol) and 5%platinum on charcoal (50 mg) in ethanol (20 mL) was stirred under aballoon of hydrogen at room temperature for 30 minutes. The resultantmixture was filtered, and concentrated under vacuum to provide thetitled compound.

¹HNMR (400 MHz, CDCl₃) δ 7.38 (dd, J=6.8, 2.0 Hz, 1H), 7.24-7.19 (m,1H), 7.11 (t, J=8.8 Hz, 1H), 4.69 (s, 2H), 4.02 (s, 3H), 3.62 (s, 3H),3.37 (t, J=6.1 Hz, 2H), 2.7-2.6 (m, 4H), 1.15 (t, J=7.3 Hz, 3H).

ES MS M+1=379.

Step 3:2-(3-Chloro-4-fluorobenzyl)-5-ethyl-8-hydroxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione

A solution of2-(3-chloro-4-fluorobenzyl)-5-ethyl-8-methoxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione(55 mg, 0.15 mmol) and 33% HBr in acetic acid (5 mL) in acetic acid (10mL) was stirred at room temperature overnight. The product mixture wasconcentrated under vacuum. The residue was subjected to preparativereverse phase HPLC purification. Collection and lyophilization ofappropriate fractions provide the titled compound.

¹HNMR (400 MHz, CDCl₃) δ 7.36 (dd, J=6.4, 2.0 Hz, 1H), 7.20 (m, 1H),7.13 (t, J=8.4 Hz, 1H), 4.66 (s, 2H), 3.66 (s, 3H), 3.44 (t, J=6.1 Hz,2H), 2.78 (t, J=6.1 Hz, 2H), 2.65 (q, J=7.3 Hz, 2H), 1.15 (t, J=7.3 Hz,3H). ES MS M+1=365.

EXAMPLE 842-(3-Chloro-4-fluorobenzyl)-5-cyclopropyl-8-hydroxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione

To a cold (0° C.) solution of2-(3-chloro-4-fluorobenzyl)-5-vinyl-8-methoxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione(0.12 g, 0.32 mmol; Example 83, step 2) in diethyl ether (5 mL), asolution of diazomethane (−3 mmol) in diethyl ether was added. Catalyticamount of palladium (II) acetate was added and the mixture was stirredat the same temperature for 30 minutes. The product mixture was filteredand concentrated under vacuum. The residue was subjected to preparativereverse phase HPLC purification. Collection and lyophilization ofappropriate fractions provide the cyclopropanation intermediate.Following the demethylation procedure described in Example 83, step 3,the above intermediate was converted to the titled compound.

¹HNMR (400 MHz, CDCl₃) δ 12.77 (s, 1H), 7.35 (dd, J=6.4, 2.0 Hz, 1H),7.20 (m, 1H), 7.13 (t, J=8.4 Hz, 1H), 4.66 (s, 2H), 3.73 (s, 3H), 3.41(t, J=6.0 Hz, 2H), 2.90 (t, J=6.0 Hz, 2H), 1.68 (m, 1H), 1.12 (q, J=8.2Hz, 2H), 0.62 (q, J=8.2 Hz, 2H). ES MS M+1=377.

EXAMPLE 852-(3-Chloro-4-fluorobenzyl)-8-hydroxy-6-methyl-5-pyridin-3-yl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione

A mixture of5-bromo-2-(3-chloro-4-fluorobenzyl)-8-hydroxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione(35 mg, 0.08 mmol; Example 80), tetrakis(triphenylphosphine)palladium(0)(5 mg), pyridine-3-boronic acid (15 mg, 0.13 mmol), aq sodium carbonate(2 M, 0.5 mL), and dioxane (1.5 mL) was heated in a microwave oven at100° C. for 15 minutes. The product mixture was concentrated undervacuum, and the residue was partitioned between water anddichloromethane. The organic extract was separated, concentrated undervacuum. The residue was subjected to preparative reverse phase HPLCpurification. Collection and lyophilization of appropriate fractionsprovide the titled compound.

¹HNMR (400 MHz, CDCl₃) δ 13.06 (br s, 1H), 8.74 (d, J=3.3 Hz, 1H), 8.51(d, J=1.5 Hz, 1H), 7.58 (d, J=7.9 Hz, 1H), 7.46 (m, 1H), 7.34 (dd,J=6.8, 2.0 Hz, 1H), 7.21-7.18 (m, 1H), 7.12 (t, J=8.6 Hz, 1H), 4.70 (d,J=14.6 Hz, 1H), 4.61 (d, J=14.6 Hz, 1H), 3.34 (m, 2H), 2.43 (m, 2H).

ES MS M+1=414

The compounds in the following table were prepared in accordance withthe procedure set forth in Example 85, using the appropriate reagents.

ES MS Example R^(G) Name (M + 1) 86

2-(3-chloro-4-fluorobenzyl)-8- hydroxy-6-methyl-5-pyridin-4-yl-2,3,4,6-tetrahydro-2,6- naphthyridine-1,7-dione 414 87

2-(3-chloro-4-fluorobenzyl)-8- hydroxy-6-methyl-5-(2-furyl)-2,3,4,6-tetrahydro-2,6- naphthyridine-1,7-dione 403

EXAMPLE 88

Oral Compositions

As a specific embodiment of an oral composition of a compound of thisinvention, 50 mg of compound of Example 1 is formulated with sufficientfinely divided lactose to provide a total amount of 580 to 590 mg tofill a size 0 hard gelatin capsule. Encapsulated oral compositionscontaining any one of the compounds disclosed in the other examples canbe similarly prepared.

EXAMPLE 89

HIV Integrase Assay: Strand Transfer Catalyzed by Recombinant Integrase

Assays for the strand transfer activity of integrase were conducted inaccordance with WO 02/30930 for recombinant integrase. Representativecompounds of the present invention exhibit inhibition of strand transferactivity in this assay. For example, the compounds in Examples 1-15,17-71, and 73-87 were tested in the integrase assay and were found tohave IC₅₀'s less than about 1 micromolar.

Further description on conducting the assay using preassembled complexesis found in Wolfe, A. L. et al., J. Virol. 1996, 70: 1424-1432, Hazudaet al., J. Virol. 1997, 71: 7005-7011; Hazuda et al., Drug Design andDiscovery 1997, 15: 17-24; and Hazuda et al., Science 2000, 287:646-650.

EXAMPLE 90

Assay for Inhibition of HIV Replication

Assays for the inhibition of acute HIV infection of T-lymphoid cellswere conducted in accordance with Vacca, J. P. et al., Proc. Natl. Acad.Sci. USA 1994, 91: 4096. Representative compounds of the presentinvention exhibit inhibition of HIV replication in this assay. Forexample, the compounds in Examples 1-15, 17-71, and 73-87 were found tohave IC₉₅'s equal to or less than about 10 micromolar in the presentassay.

EXAMPLE 916-(3-Chloro-4-fluorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamideStep 1: 1-(3-Chloro-4-fluorobenzyl)piperidin-2-one

Valerolactam (60 g) was dissolved in MTBE (1.5 L) at room temperature.To this solution was added Bu₄NSO₄ (4.9 g) as a phase transfer catalyst.The cloudy solution was stirred at room temperature for 5 minutes. Then,NaOH (50 wt %; 300 mL) was slowly added as to keep the internaltemperature below 30° C. 3-Chloro-4-fluorobenzyl bromide (108.3 g) wasthen added slowly to this biphasic mixture, again as to keep theinternal temperature under control. The reaction was then aged for 4hours at room temperature. At this time LC showed the reaction to becomplete. Water (500 mL) was then added. After phase cut, the organiclayer was washed with brine (300 mL), dried under MgSO₄ followed bysolvent switch to heptane (400 mL). The slurry obtained was stirred atroom temperature. for 1 hour and then filtered to afford the titleproduct.

Step 2: Preparation of an Unsaturated Sulfide of Formula 1:

1-(3-Chloro-4-fluorobenzyl)piperidin-2-one (25 g) was dissolved in THF(250 mL) and cooled to −20 degrees C. under nitrogen atmosphere. LHMDS(204 mL, 1M in THF) was added over 40 minutes at −20 to −30° C. and agedfor 1 hour at −20° C. Methyl benzene sulfinate (17.78 g) was added over30 minutes, again keeping the internal temperature at −20° C. Thereaction was aged for 30 minutes at −20° C. at which time LC showed thereaction to be complete. The reaction mixture was then quenched withwater (100 mL) and diluted with EtOAc (300 mL). After phase cut, theorganic layer was washed with HCl 2N (2×100 mL). The organic layer wasthen washed with brine (2×100 mL), dried under MgSO₄ followed by solventswitch to DCM (600 mL; final volume 400 mL). To this solution was addedacetic anhydride (11.6 mL) and MeSO₃H (3.07 mL). The solution was thenaged at room temperature overnight. The reaction was quenched with water(300 mL) and cooled to 0° C. The slurry obtained was then carefullybasified to pH=8 with solid Na₂CO₃. The organic layer obtained afterphase cut was then washed with brine and dried under MgSO₄. Afterevaporation of solvents, the title unsaturated sulfide 1 was obtained asan oil which solidified on standing. The title sulfide 1 can becrystallized from MeOH.

Step 3: Preparation of a Vinyl Sulfoxide of Formula 2:

Unsaturated sulfide 1 (35.47 g) was dissolved in MeOH (200 mL) and waterwas added (50 mL) followed by the addition of solid NaIO₄ (39.82 g). Theslurry obtained was stirred at room temperature for 3 days. The slurrywas then filtered and the solid obtained was washed with EtOAc (200 mL).The filtrate was then evaporated until almost dryness and diluted withEtOAc (350 mL) and washed with H₂O (200 mL). The organic layer was thenwashed with brine (200 mL) and dried under MgSO₄. The organic solventswere then removed to completion. The oil obtained was crystallized witha IPAc:Hexane (1:1.2) mixture and seeding to afford the title sulfoxide2.

Step 4: Preparation of a Michael Adduct of Formula 3:

To a solution of vinyl sulfoxide 2 (5 g, 13.74 mmoles) in THF (70 mL) at0° C. was added diphenylketimine glycine ethyl ester (4 g, 15.mmoles)followed by t-BuOLi (0.2 g, 2.5 mmoles). The mixture was stirred for 20minutes at 0° C. then, HCl 2N (80 mL) was added. The resulting mixturewas stirred at 20° C. for 20 minutes and MTBE (160 mL) was added. Afterphase separation, the aqueous layer was basified to pH=8-9 by additionof solid Na₂CO₃. The resulting aqueous layer was extracted twice withEtOAc (2×100 mL) and the solvent evaporated under reduced pressure togive the title adduct 3 as an oil.

Step 5: Preparation of an Oxamate of Formula 4:

To a solution of adduct 3 (6.2 g, 13.28 mmoles) in THF (70 mL) at 0° C.was added triethylamine (2 mL, 14.6 mmoles) followed by dropwiseaddition of ethyloxalyl chloride (1.55 mL, 13.94 mmoles). The resultingslurry was stirred for 20 minutes at 0° C., then water (50 mL) wasadded. The mixture was extracted with EtOAc (2×1100 mL), then solventswitched to toluene (final volume: 80 mL). The toluene solution washeated to 90° C. for 30-45 minutes then passed through a plug of silicagel (50 g) using EtOAc/hexanes 1:1 (200 mL), then EtOAc as eluent. Afterevaporation of the solvents, the title oxamate 4 was obtained.

Step 6: Ethyl6-(3-chloro-4-fluorobenzyl)-3,4-dihydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate

To a solution of oxamate 4 (2 g, 4.5 mmoles) in THF (35 mL) was addedLiBr (1.2 g, 18.1 mmoles) followed by DABCO (0.76 g, 6.8 mmoles). Themixture was stirred for 18 hours at 20° C., then HCl 2N (50 mL) wasadded and the mixture was extracted with EtOAc (50 mL). Solvents wereevaporated under reduced pressure to give the title compound as a paleyellow solid.

Alternative Route:

Ethyl6-(3-chloro-4-fluorobenzyl)-3,4-dihydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate

To a stirred solution of ethyl6-(3-chloro-4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate(5.0 g; see Example 12, Step 6) and sodium acetate (0.89 g) in aceticacid (90 mL) was added peracetic acid (28 mL). The mixture was thenheated at 50° C. overnight. The mixture was cooled to 5° C. andsaturated NaHSO₄ (17 mL) added, keeping the temperature at less than 25°C. The mixture was concentrated to 50% original volume and partitionedbetween tert-butyl methyl ether (100 mL) and water (50 mL). The organicphase collected and the volatiles evaporated. The residue was dissolvedin toluene (50 mL) and volatiles evaporated, the residue dissolved intoluene (50 mL) and evaporation repeated. Finally the residue wasdissolved in toluene (20 mL). Acetic anhydride (3.9 mL) was added andthe mixture heated at reflux until complete by HPLC analysis. Themixture cooled to ambient temperature and sodium ethoxide in ethanol (20mL) was added. The reaction mixture stirred overnight. 2N HCl (31 mL)was added and the title product isolated by filtration.

¹H NMR (400 MHz, CDCl₃) δ 9.6-9.5 (bs, 1H), 7.4 (dd, J=6.8. 2.4 Hz, 1H),7.2 (m, 1H), 7.15 (t, J=8.4 Hz, 1H), 4.7 (s, 2H), 4.35 (q, J=7.2 Hz,2H), 3.45 (t, J=6.4 Hz, 2H), 3.35 (t, J=6.4 Hz, 2H), 1.4 (t, J=7.2 Hz,3H) ppm.

Step 7: Methyl6-(3-chloro-4-fluorobenzyl)-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate

To a stirred suspension of ethyl6-(3-chloro-4-fluorobenzyl)-3,4-dihydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate(40 g) in DMF (200 mL) was added magnesium methoxide in methanol (100mL). The mixture heated at 40-50° C. for 3 hours. The excess methanoldistilled off, and methyl tosylate (18 mL) was added. The reactionmixture was heated at 50° C. overnight, then cooled to 25° C., and thenquenched into 1N HCl (100 mL). The suspension stirred for 1 hour atambient temperature. The product was isolated by filtration, and thefilter cake washed with water (2×100 mL) and then dried on the filterunder an atmosphere of nitrogen. The crude product was suspended inmethanol (460 mL), heated at reflux temperature for 1 hour, and thenallowed to cool to ambient temperature. The product was isolated byfiltration and the filter cake washed with cold methanol (2×40 mL) anddried to give the title product.

¹H NMR (400 MHz, CDCl₃) δ 13.37 (s, 1H), 7.35 (dd, J=2.4, 6.9 Hz, 1H),7.22-7.18 (m, 1H), 7.13 (t, J=8.4 Hz, 1H), 4.67 (s, 2H), 3.92 (s, 3H),3.54 (s, 3H), 3.43 (t, J=6.4 Hz, 2H), 2.81 (t, J=6.4 Hz, 2H) ppm. (ES MSM+1=395.0)

Step 8:6-(3-Chloro-4-fluorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

To THF (80 mL) cooled to −10° C. was added iPrMgCl (2M in THF, 60 mL).Dimethylamine (2M in THF) was then added at −10 to 0° C., the mixturethen stirred for 1 hour at −5 to −10° C. The resulting suspension ofClMgNMe₂ at −10° C. was allowed to warm to 0° C., and a solution ofmethyl6-(3-chloro-4-fluorobenzyl)-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate(10.0 g) in dichloromethane (100 mL) was added over 20 minutes at 0° C.The mixture was then stirred until reaction was complete by HPLC. Thereaction mixture was quenched with 1N HCl (335 mL). The organic layerwas collected and the aqueous layer extracted with CH₂Cl₂ (35 mL). Theorganic phases were then combined and washed with brine (35 mL).Volatiles were evaporated to give the title product as an amorphoussolid.

¹H NMR (400 MHz, CD₃OD) δ 7.46 (dd, J=2.2, 7.14 Hz, 1H), 7.33-7.29 (m,1H), 7.17 (t, J=9.0 Hz, 1H), 4.72 (d, J=14.8 Hz, 1H), 4.65 (d, J=14.8Hz, 1H), 3.35 (s, 3H), 3.33-3.96 (m, 2H), 3.07 (s, 3H), 2.97 (s, 3H),2.47 (dd, J=5.68,11.36 Hz, 2H) ppm. (ES MS M+1=408.0)

EXAMPLE 926-(3-Chloro-4-fluorobenzyl)-4-hydroxy-2-isopropyl-N,N-dimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamideStep 1: Preparation of a Michael Adduct of Formula 5:

To a solution of vinyl sulfoxide 2 (5 g, 13.74 mmoles; Example 91, Step3) in THF (70 mL) at 0° C. was added diphenylketimine glycine dimethylamide (4 g, 15.mmoles) followed by t-BuOLi (0.2 g, 2.5 mmoles). Themixture was stirred for 20 minutes at 0° C., and then HCl 2N (80 mL) wasadded. The resulting mixture was stirred at 20° C. for 20 minutes andMTBE (160 mL) was added. After phase separation, the aqueous layer wasbasified to pH=8-9 by addition of solid Na₂CO₃. The resulting aqueouslayer was extracted twice with EtOAc (2×100 mL) and the solventevaporated under reduced pressure to give the title adduct as an oil.

Step 2: Preparation of an Isopropyl Amine of Formula 6:

To a solution of adduct 5 (2.5 g, 5.35 mmoles) in MeOH (30 mL) was addedacetone (0.8 mL, 10.7 mmoles) followed sodium triacetoxyborohydride (1.2g, 5.9 mmoles). The mixture was stirred for 20 minutes, and then water(10 mL) and NaHCO₃ saturated (30 mL) were added. The resulting mixturewas extracted twice with EtOAc (2×30 mL) and the solvent evaporatedunder reduced pressure to provide the crude title product.

Step 3: Preparation of an Oxamate of Formula 7:

Crude amine 6 (5 mmol) is dissolved in THF (40 mL) at 0° C. andtriethylamine (1.4 mL, 2.2 eq.) was added followed by dropwise additionof ethyloxalyl chloride (1 mL, 2.1 eq.). The resulting slurry wasstirred for 20 minutes at 0° C., then water (30 mL) was added. Themixture was extracted with EtOAc (2×40 mL), then solvent switched totoluene (final volume: 20 mL). The toluene solution was heated at 90° C.for 3045 minutes then passed through a plug of silica gel (20 g) usingEtOAc/hexanes 1:1 (200 mL), then EtOAc as eluant. The title oxamate 7was obtained after evaporation of the solvents.

Step 4:6-(3-Chloro-4-fluorobenzyl)-4-hydroxy-2-isopropyl-N,N-dimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

To a solution of oxamate 7 (160 mg) in THF (3 mL) was added LiBr (110mg, 4 eq.) followed by DABCO (56 mg, 1.5 eq.). The mixture was stirredfor 10 minutes at room temperature, then HCl 2N (5 mL) was added and themixture was extracted with EtOAc (5 mL). The solvents were evaporatedunder reduced pressure to give the title compound.

EXAMPLE 93 Crystalline sodium salt of6-(3-chloro-4-fluorobenzyl)-4-hydroxy-2-isopropyl-N,N-dimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

Part A: Preparation

MeOH (10 mL) and MTBE (50 mL) were added to6-(3-chloro-4-fluorobenzyl)-4-hydroxy-2-isopropyl-N,N-dimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide(6.94 g). NaOH/MeOH (1 N, 15.95 mL) was then charged thereto, and theadmixture stirred until the carboxamide dissolved. The solution wasfiltered and additional MTBE (65 mL) was added to the filtrate. Thefiltrate was concentrated by removal of MeOH under vacuum (190 mm Hg at40° C.). The resulting concentrate (140 mL) was seeded, heated to 40°C., and aged overnight. The aged concentrate was then cooled to roomtemperature, and the resulting solids were separated by filtration,washed with 10% MeOH/MTBE, and vacuum dried at room temperature toafford a crystalline sodium salt.

Part B: Characterization

An XRPD pattern of a Na salt prepared in the manner described in Part Awas generated on a Philips Analytical X'Pert Pro X-ray powderdiffractometer using a continuous scan from 2.5 to 40 degrees 2 Θ.Copper K-Alpha 1 (K_(α1)) and K-Alpha 2 (K_(α2)) radiation was used asthe source. The experiment was run under ambient conditions. 2Θ valuesand the corresponding d-spacings in the XRPD pattern include thefollowing: Peak No. d-spacing (Å) 2 Theta 1 15.0 5.9 2 8.1 10.9 3 7.112.5 4 6.6 13.3 5 5.7 15.5 6 5.0 17.6 7 4.7 18.7 8 4.2 21.3 9 3.7 23.9

A Na salt prepared in the manner described in Part A was also analyzedby a TA Instruments DSC 2910 differential scanning calorimeter at aheating rate of 10° C./min from room temperature to 250° C. in a closedpan in a nitrogen atmosphere. The DSC curve exhibited an endotherm witha peak temperature of 220° C. and an associated heat of fusion of 27J/gm. The endotherm is believed to be due to melting.

A thermogravimetric analysis was performed with a Perkin-Elmer Model TGA7 under nitrogen at a heating rate of 10° C./min from room temperatureto 250° C. The TG curve showed a 1.1% weight loss from 20 to 220° C.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, thepractice of the invention encompasses all of the usual variations,adaptations and/or modifications that come within the scope of thefollowing claims.

1. A compound according to claim 20 which is a compound of Formula II,or a pharmaceutically acceptable salt thereof:

wherein: bond

in the ring is a single bond or a double bond; X¹ and X² are eachindependently: (1) —H, (2) —C₁₋₆alkyl, (3) —OH (4) —O—C₁₋₆ alkyl, (5)—C₁₋₆ haloalkyl, (6) —O—C₁₋₆ haloalkyl, (7) halogen, (8) —CN, (9)—N(R^(a))R^(b), (10) —C(═O)N(R^(a))R^(b), (11) —SR^(a), (12) —S(O)R^(a),(13) SO₂R^(a), (14) —N(R^(a))SO₂R^(b), (15) —N(R^(a))SO₂N(R^(a))R^(b),(16) —N(R^(a))C(═O)R^(b), (17) —N(R^(a))C(═O)—C(═O)N(R^(a))R^(b), (18)—HetA, (19) —C(═O)—HetA, or (20) HetB; wherein each HetA isindependently a C₄₋₅ azacycloalkyl or a C₃₋₄ diazacycloalkyl, either ofwhich is optionally substituted with 1 or 2 substituents each of whichis independently oxo or C₁₋₆ alkyl; and with the proviso that when HetAis attached to the rest of the compound via the —C(═O)— moiety, the HetAis attached to the —C(═O)— via a ring N atom; and each HetB isindependently a 5- or 6-membered heteroaromatic ring containing from 1to 4 heteroatoms independently selected from N, O and S, wherein theheteroaromatic ring is optionally substituted with from 1 to 4substituents each of which is independently halogen, —C₁₋₆ alkyl, —C₁₋₆haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, or hydroxy; oralternatively X¹ and X² are respectively located on adjacent carbons inthe phenyl ring and together form methylenedioxy or ethylenedioxy; X³is: (1) —H, (2) —C₁₋₆ alkyl, (3) —O—C₁₋₆ alkyl, (4) —C₁₋₆ haloalkyl, (5)—O—C₁₋₆ haloalkyl, or (6) halogen; R⁴ is: (1) —C₁₋₆ alkyl, (2)—CO₂R^(a), (3) —C(═O)N(R^(a))R^(b), (4) —C(═O)—N(R^(a))—(CH₂)₂₋₃—OR^(b),(5) —N(R^(a))C(═O)R^(b), (6) —N(R^(a))SO₂R^(b), (7) —C₃₋₆ cycloalkyl,which is optionally substituted with from 1 to 4 substituents each ofwhich is independently halogen, —C₁₋₆ alkyl, —CF₃, —O—C₁₋₆ alkyl, or—OCF₃, (8) —HetK, (9) —C(═O)—HetK, (10) —C(═O)N(R^(a))—HetK, (11)—C(═O)N(R^(a))—(CH₂)₀₋₂—(C₃₋₆ cycloalkyl), wherein the cycloalkyl isoptionally substituted with from 1 to 4 substituents each of which isindependently halogen, —C₁₋₆ alkyl, —CF₃, —O—C₁₋₆ alkyl, or —OCF₃, or(12) —C(═O)N(R^(a))—CH₂-phenyl, wherein the phenyl is optionallysubstituted with from 1 to 4 substituents each of which is independently—C₁₋₆ alkyl, —O—C₁₋₆ alkyl, —CF₃, —OCF₃, or halogen; (13) —HetL, (14)—C(═O)N(R^(a))R^(c), or (15) halogen; wherein HetK is a 5- or 6-memberedsaturated heterocyclic ring containing a total of from 1 to 4heteroatoms independently selected from 1 to 4 N atoms, from 0 to 2 Oatoms, and from 0 to 2 S atoms, wherein the heterocyclic ring isoptionally substituted with (i) from 1 to 4 substituents each of whichis independently —C₁₋₆ alkyl, oxo, halogen, —C(═O)N(R^(a))R^(b),—C(═O)C(═O)N(R^(a))R^(b), —C(═O)R^(a), —CO₂R^(a), —SO₂R^(a), or—SO₂N(R^(a))R^(b) and (ii) from zero to 1 C₃₋₆ cycloalkyl; and with theproviso that when HetK is attached to the rest of the compound via the—C(═O)— moiety, the HetK is attached to the —C(═O)— via a ring N atom;wherein HetL is a 5- or 6-membered heteroaromatic ring containing from 1to 4 heteroatoms independently selected from N, O and S, wherein theheteroaromatic ring is optionally substituted with from 1 to 4substituents each of which is independently —C₁₋₆ alkyl or —OH; R⁵ is:(1) —H, (2) —C₁₋₆ alkyl, (3) —C₃₋₆ cycloalkyl, (4) —(CH₂)₁₋₂—C₃₋₆cycloalkyl, (5) —CH₂-phenyl wherein the phenyl is optionally substitutedwith from 1 to 4 substituents each of which is independently halogen,C₁₋₆ alkyl, C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, or —O—C₁₋₆ haloalkyl, (6)—(CH₂)₁₋₂—HetD, wherein HetD is a 4- to 7-membered saturatedheterocyclic ring containing from 1 to 2 heteroatoms independentlyselected from 1 to 2 N atoms, from zero to 1 O atom and from zero to 1 Satom, wherein the heterocyclic ring is attached to the rest of themolecule via a ring N atom, and the heterocyclic ring is optionallysubstituted with from 1 to 4 substituents each of which is independently—C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, oxo,—C(═O)N(R^(a))R^(b), —C(═O)R^(a), —CO₂R^(a), —SO₂R^(a), or—SO₂N(R^(a))R^(b), (7) phenyl which is optionally substituted with from1 to 4 substituents each of which is independently —C₁₋₆ alkyl, —O—C₁₋₆alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ haloalkyl, —OH, halogen, —CN, —NO₂,—C(═O)R^(a), —CO₂R^(a), —SO₂R^(a), —N(R^(a))C(═O)—C₁₋₆ haloalkyl,—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)N(R^(a))R^(b), —N(R^(a))CO₂R^(b),—N(R^(a))SO₂R^(b), —C(═O)N(R^(d))R^(e), or —SO₂N(R^(d))R^(e); (8) a 5-or 6-membered heteroaromatic ring containing from 1 to 4 heteroatomsindependently selected from N, O and S, wherein the heteroaromatic ringis optionally substituted with from 1 to 4 substituents each of which isindependently —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆haloalkyl, or —OH, (9) C₁₋₆ alkyl substituted with —O—C₁₋₆ alkyl, —CN,—N(R^(a))R^(b), —C(═O)N(R^(a))R^(b), —C(═O)R^(a), —CO₂R^(a), —SO₂R^(a),or —SO₂N(R^(a))R^(b), or (10) —C₁₋₆ haloalkyl; each R^(a) isindependently H or C₁₋₆ alkyl; each R^(b) is independently H or C₁₋₆alkyl; R^(c) is C₁₋₆ haloalkyl or C₁₋₆ alkyl substituted with —CO₂R^(a),—SO₂R^(a), —SO₂N(R^(a))R^(b), or N(R^(a))R^(b); and each R^(d) and R^(e)are independently H or C₁₋₆ alkyl, or together with the N atom to whichthey are attached form a 4- to 7-membered saturated heterocyclic ringoptionally containing a heteroatom in addition to the nitrogen attachedto R^(d) and R^(e) selected from N, O, and S, wherein the S isoptionally oxidized to S(O) or S(O)₂, and wherein the saturatedheterocyclic ring is optionally substituted with from 1 to 4substituents each of which is independently halogen, —CN, —C₁₋₆ alkyl,—OH, oxo, —O—C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —C(═O)R^(a), —CO₂R^(a),—SO₂R^(a), or —SO₂N(R^(a))R^(b).
 2. The compound according to claim 1,or a pharmaceutically acceptable salt thereof, wherein: bond

in the ring is a single bond; X¹ and X² are each independently: (1) —H,(2) —C₁₋₄ alkyl, (3) —C₁₋₄ haloalkyl, (4) —OH, (5) —O—C₁₋₄ alkyl, (6)halogen, (7) —CN, (8) —C(═O)NH₂, (9) —C(═O)NH(—C₁₋₄ alkyl), (10)—C(═O)N(—C₁₋₄ alkyl)₂, or (11) —SO₂—C₁₋₄ alkyl; or alternatively X¹ andX² are respectively located on adjacent carbons in the phenyl ring andtogether form methylenedioxy or ethylenedioxy; X³ is —H, halogen, —C₁₋₄alkyl, or —O—C₁₋₄ alkyl; R⁴ is: (1) —C₁₋₄ alkyl, (2) —CO₂H, (3)—C(═O)—O—C₁₋₄ alkyl, (4) —C(═O)NH₂, (5) —C(═O)NH—C₁₋₅ alkyl, (6)—C(═O)N(C₁₋₄ alkyl)₂, (7) —C(═O)—NH—(CH₂)₂₋₃—O—C₁₋₄ alkyl, (8)—C(═O)—N(C₁₋₄ alkyl)-(CH₂)₂₋₃—O—C₁₋₄ alkyl, (9) —NHC(═O)—C₁₋₄ alkyl,(10) —N(C₁₋₄ alkyl)C(═O)—C₁₋₄ alkyl, (11) —NHSO₂—C₁₋₄ alkyl, (12)—N(C₁₋₄ alkyl)SO₂—C₁₋₄ alkyl, (13) —C₃₋₆ cycloalkyl, (14) —HetK whereinHetK is:

wherein the asterisk * denotes the point of attachment to the rest ofthe compound, (15) —C(═O)—HetK, wherein HetK is:

wherein the asterisk * denotes the point of attachment to the rest ofthe compound, (16) —C(═O)NH-HetK or —C(═O)N(C₁₋₄ alkyl)-HetK, whereinHetK is a saturated heterocyclic selected from the group consisting ofpyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, andthiomorpholinyl, wherein the saturated heterocyclic is optionallysubstituted with from 1 to 2 substituents each of which is independently—C₁₋₄ alkyl, SO₂—C₁₋₄ alkyl, or —SO₂N(C₁₋₄ alkyl)₂, (17)—C(═O)NH—(CH₂)₀₋₁—(C₃₋₆ cycloalkyl), (18) —C(═O)N(C₁₋₄alkyl)-(CH₂)₀₋₁—(C₃₋₆ cycloalkyl), (19) —C(═O)NH—CH₂-phenyl, wherein thephenyl is optionally substituted with 1 or 2 substituents each of whichis independently halogen, —C₁₋₄ alkyl, —CF₃, —O—C₁₋₄ alkyl, or —OCF₃,(20) —C(═O)N(C₁₋₄ alkyl)-CH₂-phenyl, wherein the phenyl is optionallysubstituted with 1 or 2 substituents each of which is independentlyhalogen, —C₁₋₄ alkyl, —CF₃, —O—C₁₋₄ alkyl, or —OCF₃, (21) —HetL, whereinHetL is a heteroaromatic ring which is pyrrolyl, thienyl, furanyl,imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl,triazolyl, tetrazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, orpyrazinyl, wherein the heteroaromatic ring is optionally substitutedwith from 1 to 4 substituents each of which is independently halogen or—C₁₋₄ alkyl, (22) —C(O)N(H)—C₁₋₄ haloalkyl, (23) —C(O)N(C₁₋₄ alkyl)-C₁₋₄haloalkyl, (24) —C(O)N(H)—(CH₂)₁₋₂SO₂—C₁₋₄ alkyl, (25) —C(O)N(C₁₋₄alkyl)-(CH₂)₁₋₂SO₂—C₁₋₄ alkyl, (26) —C(O)N(H)—(CH₂)₁₋₂N(C₁₋₄ alkyl)₂,(27) —C(O)N(C₁₋₄ alkyl)-(CH₂)₁₋₂N(C₁₋₄ alkyl)₂, or (28) —Cl or —Br; andR⁵ is: (1) —H, (2) —C₁₋₄ alkyl, (3) —C₃₋₆ cycloalkyl, (4) —CH₂—C₃₋₆cycloalkyl, (5) —CH₂-phenyl, wherein the phenyl is optionallysubstituted with from 1 to 3 substituents each of which is independentlyhalogen, —C₁₋₄ alkyl, —CF₃, —O—C₁₋₄ alkyl, or —OCF₃, (6) —(CH₂)₁₋₂—HetD,wherein HetD is:

wherein the asterisk * denotes the point of attachment to the rest ofthe compound, (7) phenyl which is optionally substituted with —C₁₋₄alkyl, —O—C₁₋₄ alkyl, —CF₃, —OCF₃, halogen, —CN, —NO₂, —C(═O)—C₁₋₄alkyl, —C(═O)—O—C₁₋₄ alkyl, —C(O)NH₂, —C(O)N(H)—C₁₋₄ alkyl, —C(O)N(C₁₋₄alkyl)₂, —SO₂—C₁₋₄ alkyl, —SO₂NH₂, —SO₂N(H)—C₁₋₄ alkyl, —SO₂N(C₁₋₄alkyl)₂, —N(H)C(═O)—C₁₋₄ alkyl, —N(C₁₋₄ alkyl)C(═O)—C₁₋₄ alkyl,—N(H)C(═O)—CF₃, —N(C₁₋₄ alkyl)C(═O)—CF₃, —N(H)C(═O)N(H)C₁₋₄ alkyl,—N(C₁₋₄ alkyl)C(═O)N(H)C₁₋₄ alkyl, —N(H)C(═O)N(C₁₋₄ alkyl)₂, —N(C₁₋₄alkyl)C(═O)N(C₁₋₄ alkyl)₂, —N(H)C(═O)—O—C₁₋₄ alkyl, —N(C₁₋₄alkyl)C(═O)—O—C₁₋₄ alkyl, —N(H)SO₂—C₁₋₄ alkyl, —N(C₁₋₄ alkyl)SO₂—C₁₋₄alkyl,

wherein ring A is pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, or piperazinyl optionally substituted on the other ringnitrogen with methyl or SO₂—CH₃, (8) a 5- or 6-membered heteroaromaticring which is pyrrolyl, thienyl, furanyl, imidazolyl, oxazolyl,thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, or pyrazinyl, wherein the heteroaromatic ring isoptionally substituted with from 1 to 2 substituents each of which isindependently halogen or —C₁₋₄ alkyl, (9) C₁₋₄ alkyl substituted with—O—C₁₋₄ alkyl, —CN, —NH₂, —N(H)—C₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, —C(O)NH₂,—C(O)N(H)—C₁₋₄ alkyl, —C(O)N(C₁₋₄ alkyl)₂, —C(═O)—C₁₋₄ alkyl,—C(═O)—O—C₁₋₄ alkyl, —SO₂—C₁₋₄ alkyl, —SO₂NH₂, —SO₂N(H)—C₁₋₄ alkyl, or—SO₂N(C₁₋₄ alkyl)₂, or (10) —C₁₋₄ fluoroalkyl.
 3. The compound accordingto claim 1, or a pharmaceutically acceptable salt thereof, which is acompound of Formula III:

wherein: X¹ is: (1) —H, (2) bromo, (3) chloro, (4) fluoro, or (5)methoxy; X² is: (1) —H, (2) bromo, (3) chloro, (4) fluoro, (5) methoxy,(6) —C₁₋₄ alkyl, (7) —CF₃, (8) —OCF₃, (9) —CN, or (10) —SO₂(C₁₋₄ alkyl);R⁴ is: (1) —CO₂H, (2) —C(═O)—O—C₁₋₄ alkyl, (3) —C(═O)NH₂, (4)—C(═O)NH—C₁₋₄ alkyl, (5) —C(═O)N(C₁₋₄ alkyl)₂, (6)—C(═O)—NH—(CH₂)₂₋₃—O—C₁₋₄ alkyl, (7) —C(═O)—N(C₁₋₄alkyl)-(CH₂)₂₋₃—O—C₁₋₄ alkyl, (8) —NHC(═O)—C₁₋₄ alkyl, (9) —N(C₁₋₄alkyl)C(═O)—C₁₋₄ alkyl, (10) —NHSO₂—C₁₋₄alkyl, (11)—N(C₁₋₄alkyl)SO₂—C₁₋₄alkyl, (12) —C(═O)—HetK, wherein HetK is:

wherein the asterisk * denotes the point of attachment to the rest ofthe compound, (13) —C(═O)NH—(CH₂)₀₋₁—(C₃₋₆ cycloalkyl), (14)—C(═O)N(C₁₋₄ alkyl)-(CH₂)₀₋₁—(C₃₋₆ cycloalkyl), (15)—C(═O)NH—CH₂-phenyl, or (16) —C(═O)N(C₁₋₄ alkyl)-CH₂-phenyl; and R⁵ is:(1) —H, (2) —C₁₋₄ alkyl, (3) cyclopropyl, (4) cyclobutyl, (5)—CH₂-cyclopropyl, (6) —CH₂-cyclobutyl, or (7) —CH₂-phenyl.
 4. Thecompound according to claim 3, or a pharmaceutically acceptable saltthereof, wherein R⁴ is: (1) —CO₂H, (2) —C(═O)—O—C₁₋₄ alkyl, (3)—C(═O)NH₂, (4) —C(═O)NH—C₁₋₄ alkyl, (5) —C(═O)N(C₁₋₄ alkyl)₂, (6)—C(═O)—NH—(CH₂)₂₋₃—O—C₁₋₄ alkyl, (7) —C(═O)—N(C₁₋₄alkyl)-(CH₂)₂₋₃—O—C₁₋₄ alkyl, (8) —NHC(═O)—C₁₋₄ alkyl, (9) —N(C₁₋₄alkyl)C(═O)—C₁₋₄ alkyl, (10) —NHSO₂—C₁₋₄ alkyl, (11)—N(C₁₋₄alkyl)SO₂—C₁₋₄ alkyl, (12) —C(═O)—HetK, wherein HetK is:

wherein the asterisk * denotes the point of attachment to the rest ofthe compound, (13) —C(═O)NH—(CH₂)₀₋₁—(C₃₋₆ cycloalkyl), (14)—C(═O)N(C₁₋₄ alkyl)-(CH₂)₀₋₁—(C₃₋₆ cycloalkyl), (15)—C(═O)NH—CH₂-phenyl, or (16) —C(═O)N(C₁₋₄ alkyl)-CH₂-phenyl.
 5. Thecompound according to claim 3, or a pharmaceutically acceptable saltthereof, wherein R⁴ is: (1) —CO₂H, (2) —C(═O)—O—C₁₋₄ alkyl, (3)—C(═O)NH₂, (4) —C(═O)NH—C₁₋₄ alkyl, (5) —C(═O)N(C₁₋₄ alkyl)₂, (6)—C(═O)—NH—(CH₂)₂₋₃—O—C₁₋₄ alkyl, (7) —C(═O)—N(C₁₋₄alkyl)-(CH₂)₂₋₃—O—C₁₋₄ alkyl, (8) —NHC(═O)—C₁₋₄ alkyl, (9) —N(C₁₋₄alkyl)C(═O)—C₁₋₄ alkyl, (10) —NHSO₂—C₁₋₄ alkyl, (11) —N(C₁₋₄alkyl)SO₂—C₁₋₄ alkyl, (12) —C(═O)—HetK, wherein HetK is:

wherein the asterisk * denotes the point of attachment to the rest ofthe compound, (13) —C(═O)NH—(CH₂)₀₋₁—(C₃₋₆ cycloalkyl), (14)—C(═O)N(C₁₋₄ alkyl)-(CH₂)₀₋₁—(C₃₋₆ cycloalkyl), (15)—C(═O)NH—CH₂-phenyl, or (16) —C(═O)N(C₁₋₄ alkyl)-CH₂-phenyl.
 6. Thecompound according to claim 3, or a pharmaceutically acceptable saltthereof, wherein: X¹ is fluoro; X² is —H or chloro; R⁴ is: (1)—C(═O)—O—C₁₋₃ alkyl, (2) —C(═O)NH—C₁₋₃ alkyl, (3) —C(═O)N(C₁₋₃ alkyl)₂,(4) —C(═O)—N(C₁₋₃ alkyl)-(CH₂)₂—O—C₁₋₃ alkyl, (5) —N(C₁₋₃alkyl)C(═O)—C₁₋₃ alkyl, (6) —N(C₁₋₃ alkyl)SO₂—C₁₋₃ alkyl, (7)—C(═O)—HetK, wherein HetK is:

wherein the asterisk * denotes the point of attachment to the rest ofthe compound, (8) —C(═O)NH—(CH₂)₀₋₁-(cyclopropyl), (9)—C(═O)NH—(CH₂)₀₋₁-(cyclobutyl), (10) —C(═O)N(C₁₋₃alkyl)-(CH₂)₀₋₁-cyclopropyl, (11) —C(═O)N(C₁₋₃alkyl)-(CH₂)₀₋₁-cyclobutyl, (12) —C(═O)NH—CH₂-phenyl, or (13)—C(═O)N(C₁₋₃ alkyl)-CH₂-phenyl; and R⁵ is —H or —C₁₋₄ alkyl.
 7. Thecompound according to claim 6, or a pharmaceutically acceptable saltthereof, wherein: R⁴ is: (1) —C(═O)N(C₁₋₃ alkyl)₂, (2) —C(═O)—HetK,wherein HetK is:

wherein the asterisk * denotes the point of attachment to the rest ofthe compound, (3) —C(═O)N(C₁₋₃ alkyl)-(CH₂)₀₋₁-cyclopropyl, or (4)—C(═O)N(C₁₋₃ alkyl)-(CH₂)₀₋₁-cyclobutyl; and R⁵ is —C₁₋₄ alkyl.
 8. Acompound, or a pharmaceutically acceptable salt thereof, selected fromthe group consisting of: methyl6-(4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate;6-(4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;N-cyclobutyl-6-(4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;N-cyclopropyl-6-(4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(4-fluorobenzyl)-4-hydroxy-N-isopropyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(4-fluorobenzyl)-4-hydroxy-N-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylicacid;N-[6-(4-fluorobenzyl)-3,4-dihydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl]-N-methylmethanesulfonamide;N-[6-(4-fluorobenzyl)-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]-N-methylacetamide;6-(4-fluorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-2-isopropyl-N,N-dimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-2-isobutyl-N,N-dimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(4-fluorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6-tetrahydro-2,6-naphthyridine-1-carboxamide;N-cyclobutyl-6-(4-fluorobenzyl)-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;N-cyclopropyl-6-(4-fluorobenzyl)-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(4-fluorobenzyl)-4-hydroxy-N-isopropyl-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(4-fluorobenzyl)-4-hydroxy-2-methyl-3,5-dioxo-N-(2,2,2-trifluoroethyl)-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(4-fluorobenzyl)-4-hydroxy-2-methyl-N-[2-(methylsulfonyl)ethyl]-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;N,6-bis(4-fluorobenzyl)-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;2-(4-fluorobenzyl)-8-hydroxy-6-methyl-5-(piperidin-1-ylcarbonyl)-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione;6-(4-fluorobenzyl)-4-hydroxy-2-methyl-N-neopentyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;2-(4-fluorobenzyl)-8-hydroxy-5-(thiomorpholin-4-ylcarbonyl)-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione;2-(4-fluorobenzyl)-8-hydroxy-5-(piperazin-1-ylcarbonyl)-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione;4-{[6-(4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]carbonyl}-N,N-dimethylpiperazine-1-sulfonamide;2-(4-{[6-(4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]carbonyl}piperazin-1-yl)-N,N-dimethyl-2-oxoacetamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-2-isobutyl-N-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-N,N-diethyl-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;2-(3-chloro-4-fluorobenzyl)-8-hydroxy-6-methyl-5-[(4-methylpiperazin-4-yl)carbonyl]-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione;2-(3-chloro-4-fluorobenzyl)-8-hydroxy-6-methyl-5-(thiomorpholin-4-ylcarbonyl)-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione;2-(3-chloro-4-fluorobenzyl)-8-hydroxy-6-methyl-5-(piperidin-1-ylcarbonyl)-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione;6-(3-chloro-4-fluorobenzyl)-N-(cyclopropylmethyl)-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-N-cyclopropyl-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-N-ethyl-4-hydroxy-N,2-dimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N-isopropyl-N,2-dimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;2-(3-chloro-4-fluorobenzyl)-5-[(4,4-difluoropiperidin-1-yl)carbonyl]-8-hydroxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione;2-(3-chloro-4-fluorobenzyl)-8-hydroxy-6-methyl-5-(morpholin-4-ylcarbonyl)-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,2-dimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;2-(3-chloro-4-fluorobenzyl)-8-hydroxy-6-methyl-5-[(4-cyclopropylpiperazin-4-yl)carbonyl]-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione;N,N-diethyl-6-(4-fluorobenzyl)-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;N-[2-(dimethylamino)ethyl]-6-(4-fluorobenzyl)-4-hydroxy-N,2-dimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(4-fluorobenzyl)-4-hydroxy-N,2-dimethyl-N-(1-methylpiperidin-4-yl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;N,6-bis(4-fluorobenzyl)-4-hydroxy-N,2-dimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;N,N-diethyl-6-(4-fluorobenzyl)-3,4-dihydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide;6-(4-fluorobenzyl)-3,4-dihydroxy-N-isobutyl-N-methyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide;N-ethyl-6-(4-fluorobenzyl)-3,4-dihydroxy-N-methyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide;6-(4-fluorobenzyl)-3,4-dihydroxy-N-methyl-5-oxo-N-propyl-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide;6-(4-fluorobenzyl)-3,4-dihydroxy-N-isopropyl-N-methyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide;2-(4-fluorobenzyl)-7,8-dihydroxy-5-(pyrrolidin-1-ylcarbonyl)-3,4-dihydro-2,6-naphthyridin-1(2H)-one;2-(4-fluorobenzyl)-7,8-dihydroxy-5-(morpholin-4-ylcarbonyl)-3,4-dihydro-2,6-naphthyridin-1(2H)-one;4-hydroxy-N,N,2-trimethyl-3,5-dioxo-6-[3-(trifluoromethyl)benzyl]-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;4-hydroxy-N,N,2-trimethyl-3,5-dioxo-6-[4-fluoro-3-(trifluoromethyl)benzyl]-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(1,3-benzodioxol-4-ylmethyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(1,3-benzodioxol-5-ylmethyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;4-hydroxy-6-(2-methoxybenzyl)-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;4-hydroxy-6-(3-methoxybenzyl)-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;4-hydroxy-6-(3-methylbenzyl)-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3,4-dimethylbenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(2,3-dichlorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(2,4-difluorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;4-hydroxy-N,N,2-trimethyl-3,5-dioxo-6-[3-(trifluoromethoxy)benzyl]-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-fluorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(4-fluoro-3-methylbenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(2-bromo-3-chloro-4-fluorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;4-hydroxy-6-(2-methylbenzyl)-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(2-fluorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;4-hydroxy-6-(4-methylbenzyl)-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(4-chlorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;4-hydroxy-6-(4-methoxybenzyl)-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3,5-dichlorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3,4-dichlorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3,5-difluorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3,5-dimethoxybenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-methylbenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-fluoro-4-methylbenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(2,5-difluorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-2-fluorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(4-chloro-2-fluorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(5-chloro-2-fluorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(2-fluoro-3-methylbenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(5-fluoro-2-methylbenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3,5-dimethylbenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;4-hydroxy-6-(4-hydroxybenzyl)-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(4-fluoro-3-methoxybenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-methoxybenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(4-chloro-3-methylbenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3,4-difluorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(2-chloro-4-fluorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chlorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;8-hydroxy-2-(4-methoxybenzyl)-6-methyl-5-(pyrrolidin-1-ylcarbonyl)-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione;4-hydroxy-6-(4-methoxybenzyl)-N,2-dimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;methyl6-(1,3-benzodioxol-5-ylmethyl)-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(4-methylphenyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-phenyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(3-thienyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-pyridin-3-yl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-{4-[methoxycarbonyl]-phenyl}-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-[4-(amino)carbonyl-phenyl]-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-{4-[(methylamino)carbonyl]-phenyl}-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-{4-[(ethylamino)carbonyl]-phenyl}-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-{4-[(isopropylamino)carbonyl]-phenyl}-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-{4-[(dimethylamino)carbonyl]-phenyl}-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-{4-[(diethylamino)carbonyl]-phenyl}-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-{3-[(dimethylamino)carbonyl]-phenyl}-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(4-nitrophenyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-[4-(acetylamino)phenyl]-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-[4-(acetylmethylamino)phenyl]-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-[4-methyl(trifluoroacetyl)-aminophenyl]-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-{4-[(methylaminocarbonyl)-methylamino]phenyl}-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-{4-[(dimethylaminocarbonyl)-methylamino]phenyl}-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-{4-[(methoxycarbonyl)-amino]phenyl}-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-{4-[(methoxycarbonyl)methyl-amino]phenyl}-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-{4-[(methylsulfonyl)-amino]phenyl}-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-Chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-{4-[methyl(methyl-sulfonyl)amino]phenyl}-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-[4-(aminosulfonyl)phenyl]-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-[4-(methylaminosulfonyl)-phenyl]-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-[4-(morpholin-4-ylsulfonyl)-phenyl]-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-[4-(methylsulfonyl)-phenyl]-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(3-cyanophenyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(4-cyanophenyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(4-acetylphenyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-Chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(cyanomethyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(1-cyanoethyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(2-amino-2-oxoethyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(2-amino-1-methyl-2-oxoethyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(cyclopropylmethyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(cyclobutylmethyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(cyclohexylmethyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(2-methoxyethyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(2,2,2-trifluoroethyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-benzyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(4-fluorobenzyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(3-chloro-4-fluorobenzyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(2-pyrrolidin-1-ylethyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(2-morpholin-4-ylethyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(2-aminoethyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-isopropyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-isobutyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(5-chloro-4-fluoro-2-iodobenzyl)-4-hydroxy-N,N-dimethyl-2-isopropyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;6-(5-chloro-4-Fluoro-2-iodobenzyl)-4-hydroxy-N,N-dimethyl-2-isobutyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide;N-[6-(3-chloro-4-fluorobenzyl)-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]-N-methylmethanesulfonamide;N-[6-(3-chloro-4-fluorobenzyl)-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]-N-methylethanesulfonamide;N-[6-(3-chloro-4-fluorobenzyl)-4-hydroxy-2-isobutyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]-N-methylmethanesulfonamide;N-[6-(3-chloro-4-fluorobenzyl)-4-hydroxy-2-isobutyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]-N-ethylmethanesulfonamide;6-(3-chloro-4-fluorobenzyl)-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-ylnitrile;2-(3-chloro-4-fluorobenzyl)-8-hydroxy-6-methyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione;5-bromo-2-(3-chloro-4-fluorobenzyl)-8-hydroxy-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione;5-bromo-2-(3-chloro-4-fluorobenzyl)-8-hydroxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione;2-(3-chloro-4-fluorobenzyl)-8-hydroxy-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione;2-(3-chloro-4-fluorobenzyl)-8-hydroxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione;2-(3-chloro-4-fluorobenzyl)-5-ethyl-8-hydroxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione2-(3-chloro-4-fluorobenzyl)-5-cyclopropyl-8-hydroxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione;2-(3-chloro-4-fluorobenzyl)-8-hydroxy-6-methyl-5-pyridin-3-yl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione;2-(3-chloro-4-fluorobenzyl)-8-hydroxy-6-methyl-5-pyridin-4-yl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione;and2-(3-chloro-4-fluorobenzyl)-8-hydroxy-6-methyl-5-(2-furyl)-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione.9. A pharmaceutical composition comprising an effective amount of acompound according to claim 20, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.
 10. A method ofinhibiting HIV integrase in a subject in need thereof which comprisesadministering to the subject an effective amount of the compoundaccording to claim 20, or a pharmaceutically acceptable salt thereof.11. A method for preventing or treating infection by HIV or forpreventing, treating or delaying the onset of AIDS in a subject in needthereof which comprises administering to the subject an effective amountof the compound according to claim 20, or a pharmaceutically acceptablesalt thereof.
 12. (canceled)
 13. (canceled)
 14. (canceled) 15.(canceled)
 16. A process for preparing a compound of Formula IV:

which comprises: (B) contacting a compound of Formula V:

with a Grignard salt of an amine of Formula VI:HN(R^(V))R^(W)  (VI) to obtain Compound IV; wherein: bond

in the ring is a single bond or a double bond; R¹ is —C₁₋₆ alkylsubstituted with R^(J), wherein R^(J) is: (A) aryl or aryl fused to a 5-or 6-membered heteroaromatic ring containing from 1 to 4 heteroatomsindependently selected from N, O and S, wherein the aryl or fused arylis: (a) optionally substituted with from 1 to 5 substituents each ofwhich is independently: (1) —C₁₋₆ alkyl, (2) —C₁₋₆ alkyl substitutedwith —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —NO₂, —N(R^(a))R^(b), or—S(O)_(n)R^(a), (3) —C₁₋₆haloalkyl, (4) —O—C₁₋₆ alkyl, (5) halogen, (6)C(═O)N(R^(a))R^(b), or (7) —SO₂R^(a), and (b) optionally substitutedwith 1 or 2 substituents each of which is independently: (1) phenyl, (2)benzyl, or (3) —HetB; wherein each HetB is a 5- or 6-memberedheteroaromatic ring containing from 1 to 4 heteroatoms independentlyselected from N, O and S, wherein the heteroaromatic ring is optionallysubstituted with from 1 to 4 substituents each of which is independentlyhalogen, —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, or —O—C₁₋₆haloalkyl; or (B) a 5- or 6-membered heteroaromatic ring containing from1 to 4 heteroatoms independently selected from N, O and S; wherein theheteroaromatic ring is (i) optionally substituted with from 1 to 4substituents each of which is independently halogen, —C₁₋₆ alkyl, —C₁₋₆haloalkyl, —O—C₁₋₆ alkyl, or —O—C₁₋₆ haloalkyl, and (ii) optionallysubstituted with 1 or 2 substituents each of which is independently arylor —C₁₋₆ alkyl substituted with aryl; R² and R³ are each independently—H or —C₁₋₆ alkyl; R⁵ is: (1) —C₁₋₆ alkyl, (2) —C₃₋₈ cycloalkyloptionally substituted with from 1 to 4 substituents each of which isindependently —C₁₋₆ alkyl or —O—C₁₋₆ alkyl, (3) —C₁₋₆ alkyl substitutedwith C₃₋₈ cycloalkyl, wherein the cycloalkyl is optionally substitutedwith from 1 to 4 substituents each of which is independently —C₁₋₆ alkylor —O—C₁₋₆ alkyl, (4) —C₁₋₆ alkyl substituted with aryl, wherein thearyl is optionally substituted with from 1 to 5 substituents each ofwhich is independently —C₁₋₆ alkyl, —C₁₋₆ alkylene-O—C₁₋₆ alkyl, orhalogen, or (5) —C₁₋₆ alkyl substituted with a 5- or 6-memberedheteroaromatic ring containing from 1 to 4 heteroatoms independentlyselected from N, O and S, wherein the heteroaromatic ring is optionallysubstituted with from 1 to 4 substituents each of which is independently—C₁₋₆ alkyl; R^(T) is —C₁₋₆ alkyl; R^(V) and R^(W) are eachindependently —C₁₋₆ alkyl or R^(V) and R^(W) together with the N atom towhich they are both attached form a 4- to 6-membered saturatedheterocyclic ring optionally containing a heteroatom in addition to thenitrogen attached to R^(V) and R^(W) selected from N, O, and S, wherethe S is optionally oxidized to S(O) or S(O)₂, and wherein the saturatedheterocyclic ring is optionally substituted with 1 or 2 substituentseach of which is independently a C₁₋₆ alkyl group; each aryl isindependently phenyl, naphthyl, or indenyl; each R^(a) is independentlyH or C₁₋₆ alkyl; and each R^(b) is independently H or C₁₋₆ alkyl. 17.The process according to claim 16, wherein the process furthercomprises: (A) treating a compound of Formula IX:

with (i) a tertiary amine base in the presence of a lithium salt or (ii)an alkoxide base, to obtain a compound of Formula V; wherein one ofbonds

and

is a single bond and the other is a double bond; and R^(T)* is C₁₋₆alkyl.
 18. A process for preparing a compound of Formula IV:

which comprises treating a compound of Formula X:

with (i) a tertiary amine base in the presence of a lithium salt or (ii)an alkoxide base, to obtain a compound of Formula IV, wherein: bond

in the ring is a single bond or a double bond; R¹ is —C₁₋₆ alkylsubstituted with R^(J), wherein R^(J) is: (A) aryl or aryl fused to a 5-or 6-membered heteroaromatic ring containing from 1 to 4 heteroatomsindependently selected from N, O and S, wherein the aryl or fused arylis: (a) optionally substituted with from 1 to 5 substituents each ofwhich is independently: (1) —C₁₋₆ alkyl, (2) —C₁₋₆ alkyl substitutedwith —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —NO₂, —N(R^(a))R^(b), or—S(O)_(n)R^(a), (3) —C₁₋₆ haloalkyl, (4) —O—C₁₋₆ alkyl, (5) halogen, (6)C(═O)N(R^(a))R^(b), or (7) —SO₂R^(a), and (b) optionally substitutedwith 1 or 2 substituents each of which is independently: (1) phenyl, (2)benzyl, or (3) —HetB; wherein each HetB is a 5- or 6-memberedheteroaromatic ring containing from 1 to 4 heteroatoms independentlyselected from N, O and S, wherein the heteroaromatic ring is optionallysubstituted with from 1 to 4 substituents each of which is independentlyhalogen, —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, or —O—C₁₋₆haloalkyl; or (B) a 5- or 6-membered heteroaromatic ring containing from1 to 4 heteroatoms independently selected from N, O and S; wherein theheteroaromatic ring is (i) optionally substituted with from 1 to 4substituents each of which is independently halogen, —C₁₋₆ alkyl, —C₁₋₆haloalkyl, —O—C₁₋₆ alkyl, or —O—C₁₋₆ haloalkyl, and (ii) optionallysubstituted with 1 or 2 substituents each of which is independently arylor —C₁₋₆ alkyl substituted with aryl; R² and R³ are each independently—H or —C₁₋₆ alkyl; R⁵ is: (1) —C₁₋₆ alkyl, (2) —C₃₋₈ cycloalkyloptionally substituted with from 1 to 4 substituents each of which isindependently —C₁₋₆ alkyl or —O—C₁₋₆ alkyl, (3) —C₁₋₆ alkyl substitutedwith C₃₋₈ cycloalkyl, wherein the cycloalkyl is optionally substitutedwith from 1 to 4 substituents each of which is independently —C₁₋₆ alkylor —O—C₁₋₆ alkyl, (4) —C₁₋₆ alkyl substituted with aryl, wherein thearyl is optionally substituted with from 1 to 5 substituents each ofwhich is independently —C₁₋₆ alkyl, —C₁₋₆ alkylene-O—C₁₋₆ alkyl, orhalogen, or (5) —C₁₋₆ alkyl substituted with a 5- or 6-memberedheteroaromatic ring containing from 1 to 4 heteroatoms independentlyselected from N, O and S, wherein the heteroaromatic ring is optionallysubstituted with from 1 to 4 substituents each of which is independently—C₁₋₆ alkyl; R^(V) and R^(W) are each independently —C₁₋₆ alkyl or R^(V)and R^(W) together with the N atom to which they are both attached forma 4- to 6-membered saturated heterocyclic ring optionally containing aheteroatom in addition to the nitrogen attached to R^(V) and R^(W)selected from N, O, and S, where the S is optionally oxidized to S(O) orS(O)₂, and wherein the saturated heterocyclic ring is optionallysubstituted with 1 or 2 substituents each of which is independently aC₁₋₆ alkyl group; each aryl is independently phenyl, naphthyl, orindenyl; each R^(a) is independently H or C₁₋₆ alkyl; each R^(b) isindependently H or C₁₋₆ alkyl; one of bonds

and

is a single bond and the other is a double bond; and R^(T)* is C₁₋₆alkyl.
 19. A process for preparing a compound of Formula VII:

which comprises reacting an alkylating agent of formula R⁵-Z with acompound of Formula VIII:

in a polar aprotic solvent and in the presence of a base selected from amagnesium base and a calcium base; wherein: bond

in the ring is a single bond or a double bond; W is —H or —C₁₋₆ alkyl; Zis halogen or —SO₃-Q wherein Q is (i) C₁₋₆ alkyl or (ii) phenyloptionally substituted with 1 or 2 substituents each of which isindependently a C₁₋₆ alkyl; R^(S) is —O—C₁₋₆ alkyl or N(R^(V))R^(W)wherein R^(V) and R^(W) are each independently —C₁₋₆ alkyl or R^(V) andR^(W) together with the N atom to which they are both attached form a 4-to 6-membered saturated heterocyclic ring optionally containing aheteroatom in addition to the nitrogen attached to R^(V) and R^(W)selected from N, O, and S, where the S is optionally oxidized to S(O) orS(O)₂, and wherein the saturated heterocyclic ring is optionallysubstituted with 1 or 2 substituents each of which is independently aC₁₋₆ alkyl group; R¹ is —C₁₋₆ alkyl substituted with R^(J), whereinR^(J) is: (A) aryl or aryl fused to a 5- or 6-membered heteroaromaticring containing from 1 to 4 heteroatoms independently selected from N, Oand S, wherein the aryl or fused aryl is: (a) optionally substitutedwith from 1 to 5 substituents each of which is independently: (1) —C₁₋₆alkyl optionally substituted with —OH, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl,—CN, —NO₂, —N(R^(a))R^(b), —C(═O)N(R^(a))R^(b), —C(═O)R^(a), —CO₂R^(a),—S(O)_(n)R^(a), —SO₂N(R^(a))R^(b), —N(R^(a))C(═O)R^(b),—N(R^(a))CO₂R^(b), —N(R^(a))SO₂R^(b), —N(R^(a))SO₂N(R^(a))R^(b),—OC(═O)N(R^(a))R^(b), or —N(R^(a))C(═O)N(R^(a))R^(b), (2) —O—C₁₋₆ alkyl,(3) —C₁₋₆ haloalkyl, (4) —O—C₁₋₆ haloalkyl, (5) —OH, (6) halogen, (7)—CN, (8) —NO₂, (9) —N(R^(a))R^(b), (10) —C(═O)N(R^(a))R^(b), (11)—C(═O)R^(a), (12) —CO₂R^(a), (13) —SR^(a), (14) —S(═O)R^(a), (15)—SO₂R^(a), (16) —SO₂N(R^(a))R^(b), (17) —N(R^(a))SO₂R^(b), (18)—N(R^(a))SO₂N(R^(a))R^(b), (19) —N(R^(a))C(═O)R^(b), (20)—N(R^(a))C(═O)—C(═O)N(R^(a))R^(b), or (21) —N(R^(a))CO₂R^(b), and (b)optionally substituted with 1 or 2 substituents each of which isindependently: (1) phenyl, (2) benzyl, (3) —HetA, (4) —C(═O)—HetA, or(5) —HetB; wherein each HetA is independently a C₄₋₇ azacycloalkyl or aC₃₋₆ diazacycloalkyl, either of which is optionally substituted withfrom 1 to 4 substituents each of which is independently oxo or C₁₋₆alkyl; and wherein each HetB is a 5- or 6-membered heteroaromatic ringcontaining from 1 to 4 heteroatoms independently selected from N, O andS, wherein the heteroaromatic ring is optionally substituted with from 1to 4 substituents each of which is independently halogen, —C₁₋₆ alkyl,—C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, or hydroxy; or (B) a5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatomsindependently selected from N, O and S; wherein the heteroaromatic ringis (i) optionally substituted with from 1 to 4 substituents each ofwhich is independently halogen, —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆alkyl, —O—C₁₋₆ haloalkyl, or hydroxy, and (ii) optionally substitutedwith 1 or 2 substituents each of which is independently aryl or —C₁₋₆alkyl substituted with aryl; R² and R³ are each independently —H or—C₁₋₆ alkyl; R⁵ is: (1) —C₁₋₆alkyl, (2) —C₃₋₈ cycloalkyl optionallysubstituted with from 1 to 4 substituents each of which is independently—C₁₋₆ alkyl or —O—C₁₋₆ alkyl, (3) —C₁₋₆ alkyl substituted with C₃₋₈cycloalkyl, wherein the cycloalkyl is optionally substituted with from 1to 4 substituents each of which is independently —C₁₋₆ alkyl or —O—C₁₋₆alkyl, (4) —C₁₋₆ alkyl substituted with aryl, wherein the aryl isoptionally substituted with from 1 to 5 substituents each of which isindependently —C₁₋₆ alkyl, —C₁₋₆ alkylene-O—C₁₋₆ alkyl, or halogen, or(5) —C₁₋₆ alkyl substituted with a 5- or 6-membered heteroaromatic ringcontaining from 1 to 4 heteroatoms independently selected from N, O andS, wherein the heteroaromatic ring is optionally substituted with from 1to 4 substituents each of which is independently —C₁₋₆ alkyl; each arylis independently phenyl, naphthyl, or indenyl; each R^(a) isindependently H or C₁₋₆ alkyl; each R^(b) is independently H or C₁₋₆alkyl; and each n is independently an integer equal to zero, 1, or 2.20. A compound of Formula I, or a pharmaceutically acceptable saltthereof:

wherein: bond

in the ring is a single bond or a double bond; R¹ is —C₁₋₆ alkyl, R^(J),or —C₁₋₆ alkyl substituted with R^(J), wherein R^(J) is: (A) (i) aryl or(ii) aryl fused to a 5- or 6-membered heteroaromatic ring containingfrom 1 to 4 heteroatoms independently selected from N, O and S or (iii)aryl substituted on two adjacent ring carbons with alkylenedioxy,wherein the aryl or fused aryl or alkylenedioxy aryl is: (a) optionallysubstituted with from 1 to 5 substituents each of which isindependently: (1) —C₁₋₆ alkyl optionally substituted with —OH, —O—C₁₋₆alkyl, —O—C₁₋₆ haloalkyl, —CN, —NO₂, —N(R^(a))R^(b),—C(═O)N(R^(a))R^(b), —C(═O)R^(a), —CO₂R^(a), —S(O)_(n)R^(a),—SO₂N(R^(a))R^(b), —N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(b),—N(R^(a))SO₂R^(b), —N(R^(a))SO₂N(R^(a))R^(b), —OC(═O)N(R^(a))R^(b), or—N(R^(a))C(═O)N(R^(a))R^(b), (2) —O—C₁₋₆ alkyl, (3) —C₁₋₆ haloalkyl, (4)—O—C₁₋₆ haloalkyl, (5) —OH, (6) halogen, (7) —CN, (8) —NO₂, (9)—N(R^(a))R^(b), (10) —C(═O)N(R^(a))R^(b), (11) —C(═O)R^(a), (12)—CO₂R^(a), (13) —SR^(a), (14) —S(═O)R^(a), (15) —SO₂R^(a), (16)—SO₂N(R^(a))R^(b), (17) —N(R^(a))SO₂R^(b), (18)—N(R^(a))SO₂N(R^(a))R^(b), (19) —N(R^(a))C(═O)R^(b), (20)—N(R^(a))C(═O)—C(═O)N(R^(a))R^(b), (21) —N(R^(a))CO₂R^(b), or (22)—N(R^(a))C(═O)N(R^(a))R^(b), and (b) optionally substituted with 1 or 2substituents each of which is independently: (1) C₃₋₈ cycloalkyl whichis optionally substituted with from 1 to 4 substituents each of which isindependently halogen, CN, C₁₋₆ alkyl, OH, O—C₁₋₆ alkyl, C₁₋₆ haloalkyl,O—C₁₋₆ haloalkyl, C₁₋₆ alkylene-CN, C₁₋₆ alkylene-OH, or C₁₋₆alkylene-O—C₁₋₆ alkyl, (2) aryl or C₁₋₆ alkyl substituted with aryl,wherein in either case the aryl is optionally substituted with from 1 to5 substituents each of which is independently halogen, CN, NO₂, C₁₋₆alkyl, C₁₋₆ haloalkyl, OH, O—C₁₋₆ alkyl, O—C₁₋₆ haloalkyl,N(R^(a))R^(b), C(O)N(R^(a))R^(b), C(O)R^(a), C(O)OR^(a), SR^(a),S(O)R^(a), S(O)₂R^(a), S(O)₂N(R^(a))R^(b), S(O)₂N(R^(a))C(O)R^(b), C₁₋₆alkylene-CN, C₁₋₆ alkylene-NO₂, C₁₋₆ alkylene-OH, C₁₋₆ alkylene-O—C₁₋₆alkyl, C₁₋₆ alkylene-O—C₁₋₆ haloalkyl, C₁₋₆ alkylene-N(R^(a))R^(b), C₁₋₆alkylene-C(O)N(R^(a))R^(b), C₁₋₆ alkylene-C(O)R^(a), C₁₋₆alkylene-C(O)OR^(a), C₁₋₆ alkylene-SR^(a), C₁₋₆ alkylene-S(O)R^(a), C₁₋₆alkylene-S(O)₂R^(a), C₁₋₆ alkylene-S(O)₂N(R^(a))R^(b), or C₁₋₆alkylene-S(O)₂N(R^(A))C(O)R^(b), (3) —HetA, (4) —C(═O)—HetA, or (5)—HetB; wherein each HetA is independently a C₄₋₇ azacycloalkyl or a C₃₋₆diazacycloalkyl, either of which is optionally substituted with from 1to 4 substituents each of which is independently halogen, CN, C₁₋₆alkyl, OH, oxo, O—C₁₋₆ alkyl, C₁₋₆ haloalkyl, S(O)₂R^(a), C₁₋₆alkylene-CN, C₁₋₆ alkylene-OH, or C₁₋₆ alkylene-O—C₁₋₆ alkyl; andwherein each HetB is independently a 5- or 6-membered heteroaromaticring containing from 1 to 4 heteroatoms independently selected from N, Oand S, wherein the heteroaromatic ring is optionally substituted withfrom 1 to 4 substituents each of which is independently halogen, CN,NO₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, OH, O—C₁₋₆ alkyl, O—C₁₋₆ haloalkyl,N(R^(a))R^(b), C(O)N(R^(a))R^(b), C(O)R^(a), C(O)OR^(a), SR^(a),S(O)R^(a), S(O)₂R^(a), S(O)₂N(R^(a))R^(b), S(O)₂N(R^(a))C(O)R^(b), C₁₋₆alkylene-CN, C₁₋₆ alkylene-NO₂, C₁₋₆ alkylene-OH, C₁₋₆ alkylene-O—C₁₋₆alkyl, C₁₋₆ alkylene-O—C₁₋₆ haloalkyl, C₁₋₆ alkylene-N(R^(a))R^(b), C₁₋₆alkylene-C(O)N(R^(a))R^(b), C₁₋₆ alkylene-C(O)R^(a), C₁₋₆alkylene-C(O)OR^(a), C₁₋₆ alkylene-SR^(a), C₁₋₆ alkylene-S(O)R^(a), C₁₋₆alkylene-S(O)₂R^(a), C₁₋₆ alkylene-S(O)₂N(R^(a))R^(b), or C₁₋₆alkylene-S(O)₂N(R^(a))C(O)R^(b); or (B) a 5- or 6-memberedheteroaromatic ring containing from 1 to 4 heteroatoms independentlyselected from N, O and S, wherein the heteroaromatic ring is: (a)optionally substituted with from 1 to 4 substituents each of which isindependently: (1) —C₁₋₆ alkyl optionally substituted with —OH, —O—C₁₋₆alkyl, —O—C₁₋₆ haloalkyl, —CN, —NO₂, —N(R^(a))R^(b),—C(═O)N(R^(a))R^(b), —C(═O)R^(a), —CO₂R^(a), —S(O)_(n)R^(a),—SO₂N(R^(a))R^(b), —N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(b),—N(R^(a))SO₂R^(b), —N(R^(a))SO₂N(R^(a))R^(b), —OC(═O)N(R^(a))R^(b), or—N(R^(a))C(═O)N(R^(a))R^(b), (2) —O—C₁₋₆ alkyl, (3) —C₁₋₆ haloalkyl, (4)—O—C₁₋₆ haloalkyl, (5) —OH, (6) halogen, (7) —CN, (8) —NO₂, (9)—N(R^(a))R^(b), (10) —C(═O)N(R^(a))R^(b), (11) —C(═O)R^(a), (12)—CO₂R^(a), (13) —SR^(a), (14) —S(═O)R^(a), (15) —SO₂R^(a), (16)—SO₂N(R^(a))R^(b), (17) —N(R^(a))SO₂R^(b), (18)—N(R^(a))SO₂N(R^(a))R^(b), (19) —N(R^(a))C(═O)R^(b), (20)—N(R^(a))C(═O)—C(═O)N(R^(a))R^(b), (21) —N(R^(a))CO₂R^(b), or (22)—N(R^(a))C(═O)N(R^(a))R^(b), and (b) optionally substituted with 1 or 2substituents each of which is independently: (1) C₃₋₈ cycloalkyl whichis optionally substituted with from 1 to 4 substituents each of which isindependently halogen, CN, C₁₋₆ alkyl, OH, O—C₁₋₆ alkyl, C₁₋₆ haloalkyl,O—C₁₋₆ haloalkyl, C₁₋₆ alkylene-CN, C₁₋₆ alkylene-OH, or C₁₋₆alkylene-O—C₁₋₆ alkyl, (2) aryl or C₁₋₆ alkyl substituted with aryl,wherein in either case the aryl is optionally substituted with from 1 to5 substituents each of which is independently halogen, CN, NO₂, C₁₋₆alkyl, C₁₋₆ haloalkyl, OH, O—C₁₋₆ alkyl, O—C₁₋₆ haloalkyl,N(R^(a))R^(b), C(O)N(R^(a))R^(b), C(O)R^(a), C(O)OR^(a), SR^(a),S(O)R^(a), S(O)₂R^(a), S(O)₂N(R^(a))R^(b), S(O)₂N(R^(a))C(O)R^(b), C₁₋₆alkylene-CN, C₁₋₆ alkylene-NO₂, C₁₋₆ alkylene-OH, C₁₋₆ alkylene-O—C₁₋₆alkyl, C₁₋₆ alkylene-O—C₁₋₆ haloalkyl, C₁₋₆ alkylene-N(R^(a))R^(b), C₁₋₆alkylene-C(O)N(R^(a))R^(b), C₁₋₆ alkylene-C(O)R^(a), C₁₋₆alkylene-C(O)OR^(a), C₁₋₆ alkylene-SR^(a), C₁₋₆ alkylene-S(O)R^(a), C₁₋₆alkylene-S(O)₂R^(a), C₁₋₆ alkylene-S(O)₂N(R^(a))R^(b), or C₁₋₆alkylene-S(O)₂N(R^(A))C(O)R^(b), (3) —HetA, (4) —C(═O)—HetA, or (5)—HetB; wherein HetA and HetB are each independently as defined above; R²is —H or —C₁₋₆ alkyl; R³ independently has the same definition as R⁴,with the proviso that at least one of R³ and R⁴ is —H or —C₁₋₆ alkyl;or, as an alternative, when bond

is a double bond, R² and R³ together with the carbon atoms to which eachis attached form: (i) a benzene ring which is optionally substitutedwith a total of from 1 to 4 substituents wherein (a) from zero to 4substituents are each independently one of substituents (1) to (22) asdefined in part (A)(a) of the definition of R¹ and (b) from zero to 2substituents are each independently one of the substituents (1) to (5)as defined in part (A)(b) of the definition of R¹, or (ii) a 5- or6-membered heteroaromatic ring containing from 1 to 4 heteroatomsindependently selected from N, O and S, wherein the heteroaromatic ringis optionally substituted with a total of from 1 to 3 substituentswherein (a) from zero to 3 substituents are each independently one ofsubstituents (1) to (22) as defined in part (B)(a) of the definition ofR¹ and (b) from zero to 2 substituents are each independently one of thesubstituents (1) to (5) as defined in part (B)(b) of the definition ofR¹; R⁴ is: (1) —H, (2) —C₁₋₆ alkyl, (3) —C₁₋₆ haloalkyl, (4) —C₁₋₆ alkylsubstituted with —OH, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —CN,—N(R^(a))R^(b), —C(═O)N(R^(a))R^(b), —C(═O)R^(a), —CO₂R^(a),—C(═O)—N(R^(a))—C₁₋₆ alkylene-OR^(b) with the proviso that the—N(R^(a))— moiety and the —OR^(b) moiety are not both attached to thesame carbon of the —C₁₋₆ alkylene-moiety, —S(O)_(n)R^(a),—SO₂N(R^(a))R^(b), —N(R^(a))C(═O)—R^(b), —N(R^(a))CO₂R^(b),—N(R^(a))SO₂R^(b), —N(R^(a))SO₂N(R^(a))R^(b),—N(R^(a))C(═O)N(R^(a))R^(b), or —OC(═O)N(R^(a))R^(b), (5) —C(═O)R^(a),(6) —CO₂R^(a), (7) —C(═O)N(R^(a))R^(b), (8) —C(═O)—N(R^(a))—C₁₋₆alkylene-OR^(b) with the proviso that the —N(R^(a))— moiety and the—OR^(b) moiety are not both attached to the same carbon of the —C₁₋₆alkylene-moiety, (9) —N(R^(a))—C(═O)—R^(b), (10)—N(R^(a))—C(═O)—C(═O)N(R^(a))R^(b), (11) —N(R^(a))SO₂R^(b), (12)—N(R^(a))SO₂N(R^(a))R^(b), (13) —N(R^(a))C(═O)N(R^(a))R^(b), (14)—OC(═O)N(R^(a))R^(b), (15) —R^(K), (16) —C(═O)—R^(K), (17)—C(═O)N(R^(a))—R^(K), (18) —C(═O)N(R^(a))—C₁₋₆ alkylene-R^(K), (19)—C₁₋₆ alkyl substituted with —R^(K), (20) —C₁₋₆ alkyl substituted with—C(═O)—R^(K), (21) —C₁₋₆ alkyl substituted with —C(═O)N(R^(a))—R^(K),(22) —C₁₋₆ alkyl substituted with —C(═O)N(R^(a))—C₁₋₆ alkylene-R^(K),(23) —C(═O)N(R^(a))R^(c), (24) —CN, (25) halogen, (26) —N(R^(a))R^(b),or (27) —N(R^(a))CO₂R^(b); wherein R^(K) is (i)C₃₋₈ cycloalkyl which isoptionally substituted with from 1 to 4 substituents each of which isindependently halogen, CN, C₁₋₆ alkyl, OH, O—C₁₋₆ alkyl, C₁₋₆ haloalkyl,O—C₁₋₆ haloalkyl, C₁₋₆ alkylene-CN, C₁₋₆ alkylene-OH, or C₁₋₆alkylene-O—C₁₋₆ alkyl, (ii) aryl, which is optionally substituted withfrom 1 to 5 substituents each of which is independently —C₁₋₆ alkyl,—C₁₋₆ alkylene-OH, —C₁₋₆ alkylene-O—C₁₋₆ alkyl, —C₁₋₆ alkylene-O—C₁₋₆haloalkyl, —C₁₋₆ alkylene-N(R^(a))R^(b), —C₁₋₆alkylene-C(═O)N(R^(a))R^(b), —C₁₋₆ alkylene-C(═O)R^(a), —C₁₋₆alkylene-CO₂R^(a), —C₁₋₆ alkylene-S(O)_(n)R^(a), —O—C₁₋₆ alkyl, —C₁₋₆haloalkyl, —O—C₁₋₆ haloalkyl, —OH, halogen, —N(R^(a))R^(b),—C(═O)N(R^(a))R^(b), —C(═O)R^(a), —CO₂R^(a), —S(O)_(n)R^(a), or—SO₂N(R^(a))R^(b). (iii) HetK, which is a 4- to 7-membered saturatedheterocyclic ring containing at least one carbon atom and from 1 to 4heteroatoms independently selected from N, O and S, wherein theheterocyclic ring is: (a) optionally substituted with from 1 to 6substituents each of which is independently halogen, —C₁₋₆ alkyl, —C₁₋₆haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, oxo, —C(═O)N(R^(a))R^(b),—C(═O)C(═O)N(R^(a))R^(b), —C(═O)R^(a), —CO₂R^(a), —S(O)_(n)R^(a), or—SO₂N(R^(a))R^(b); and (b) optionally substituted with: (1) C₃₋₈cycloalkyl which is optionally substituted with from 1 to 4 substituentseach of which is independently halogen, CN, C₁₋₆ alkyl, OH, O—C₁₋₆alkyl, C₁₋₆ haloalkyl, O—C₁₋₆ haloalkyl, C₁₋₆ alkylene-CN, C₁₋₆alkylene-OH, or C₁₋₆ alkylene-O—C₁₋₆ alkyl, (2) aryl which is optionallysubstituted with from 1 to 5 substituents each of which is independentlyhalogen, CN, NO₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, OH, O—C₁₋₆ alkyl, O—C₁₋₆haloalkyl, N(R^(a))R^(b), C(O)N(R^(a))R^(b), C(O)R^(a), C(O)OR^(a),SR^(a), S(O)R^(a), S(O)₂R^(a), S(O)₂N(R^(a))R^(b),S(O)₂N(R^(a))C(O)R^(b), C₁₋₆ alkylene-CN, C₁₋₆ alkylene-NO₂, C₁₋₆alkylene-OH, C₁₋₆ alkylene-O—C₁₋₆ alkyl, C₁₋₆ alkylene-O—C₁₋₆ haloalkyl,C₁₋₆ alkylene-N(R^(a))R^(b), C₁₋₆ alkylene-C(O)N(R^(a))R^(b), C₁₋₆alkylene-C(O)R^(a), C₁₋₆ alkylene-C(O)OR^(a), C₁₋₆ alkylene-SR^(a), C₁₋₆alkylene-S(O)R^(a), C₁₋₆ alkylene-S(O)₂R^(a), C₁₋₆alkylene-S(O)₂N(R^(a))R^(b), or C₁₋₆ alkylene-S(O)₂N(R^(A))C(O)R^(b), or(3) HetC, wherein HetC is a 5- or 6-membered heteroaromatic ringcontaining from 1 to 4 heteroatoms independently selected from N, O andS, wherein the heteroaromatic ring is optionally fused with a benzenering, and the optionally fused heteroaromatic ring is optionallysubstituted with from 1 to 4 substituents each of which is independentlyhalogen, CN, NO₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, OH, O—C₁₋₆ alkyl, O—C₁₋₆haloalkyl, N(R^(a))R^(b), C(O)N(R^(a))R^(b), C(O)R^(a), C(O)OR^(a),SR^(a), S(O)R^(a), S(O)₂R^(a), S(O)₂N(R^(a))R^(b),S(O)₂N(R^(a))C(O)R^(b), C₁₋₆ alkylene-CN, C₁₋₆ alkylene-NO₂, C₁₋₆alkylene-OH, C₁₋₆ alkylene-O—C₁₋₆ alkyl, C₁₋₆ alkylene-O—C₁₋₆ haloalkyl,C₁₋₆ alkylene-N(R^(a))R^(b), C₁₋₆ alkylene-C(O)N(R^(a))R^(b), C₁₋₆alkylene-C(O)R^(a), C₁₋₆ alkylene-C(O)OR^(a), C₁₋₆ alkylene-SR^(a), C₁₋₆alkylene-S(O)R^(a), C₁₋₆ alkylene-S(O)₂R^(a), C₁₋₆alkylene-S(O)₂N(R^(a))R^(b), or C₁₋₆ alkylene-S(O)₂N(R^(a))C(O)R^(b), or(iv) —HetL, which is a 5- or 6-membered heteroaromatic ring containingfrom 1 to 4 heteroatoms independently selected from N, O and S, whereinthe heteroaromatic ring is optionally substituted with from 1 to 4substituents each of which is independently halogen, CN, NO₂, C₁₋₆alkyl, C₁₋₆ haloalkyl, OH, O—C₁₋₆ alkyl, O—C₁₋₆ haloalkyl,N(R^(a))R^(b), C(O)N(R^(a))R^(b), C(O)R^(a), C(O)OR^(a), SR^(a),S(O)R^(a), S(O)₂R^(a), S(O)₂N(R^(a))R^(b), S(O)₂N(R^(a))C(O)R^(b), C₁₋₆alkylene-CN, C₁₋₆ alkylene-NO₂, C₁₋₆ alkylene-OH, C₁₋₆ alkylene-O—C₁₋₆alkyl, C₁₋₆ alkylene-O—C₁₋₆ haloalkyl, C₁₋₆ alkylene-N(R^(a))R^(b), C₁₋₆alkylene-C(O)N(R^(a))R^(b), C₁₋₆ alkylene-C(O)R^(a), C₁₋₆alkylene-C(O)OR^(a), C₁₋₆ alkylene-SR^(a), C₁₋₆ alkylene-S(O)R^(a), C₁₋₆alkylene-S(O)₂R^(a), C₁₋₆ alkylene-S(O)₂N(R^(a))R^(b), or C₁₋₆alkylene-S(O)₂N(R^(a))C(O)R^(b); R⁵ is: (1) —H, (2) —C₁₋₆alkyl, (3)—C₃₋₈ cycloalkyl optionally substituted with from 1 to 4 substituentseach of which is independently halogen, CN, C₁₋₆ alkyl, OH, O—C₁₋₆alkyl, C₁₋₆ haloalkyl, O—C₁₋₆ haloalkyl, C₁₋₆ alkylene-CN, C₁₋₆alkylene-OH, or C₁₋₆ alkylene-O—C₁₋₆ alkyl, (4) —C₁₋₆ alkyl substitutedwith C₃₋₈ cycloalkyl, wherein the cycloalkyl is optionally substitutedwith from 1 to 4 substituents each of which is independently halogen,CN, C₁₋₆ alkyl, OH, O—C₁₋₆ alkyl, C₁₋₆ haloalkyl, O—C₁₋₆ haloalkyl, C₁₋₆alkylene-CN, C₁₋₆ alkylene-OH, or C₁₋₆ alkylene-O—C₁₋₆ alkyl, (5) —C₁₋₆alkyl substituted with aryl, wherein the aryl is optionally substitutedwith from 1 to 5 substituents each of which is independently halogen,CN, NO₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, OH, O—C₁₋₆ alkyl, O—C₁₋₆ haloalkyl,N(R^(a))R^(b), C(O)N(R^(a))R^(b), C(O)R^(a), C(O)OR^(a), SR^(a),S(O)R^(a), S(O)₂R^(a), S(O)₂N(R^(a))R^(b), S(O)₂N(R^(a))C(O)R^(b), C₁₋₆alkylene-CN, C₁₋₆ alkylene-NO₂, C₁₋₆ alkylene-OH, C₁₋₆ alkylene-O—C₁₋₆alkyl, C₁₋₆ alkylene-O—C₁₋₆ haloalkyl, C₁₋₆ alkylene-N(R^(a))R^(b), C₁₋₆alkylene-C(O)N(R^(a))R^(b), C₁₋₆ alkylene-C(O)R^(a), C₁₋₆alkylene-C(O)OR^(a), C₁₋₆ alkylene-SR^(a), C₁₋₆ alkylene-S(O)R^(a), C₁₋₆alkylene-S(O)₂R^(a), C₁₋₆ alkylene-S(O)₂N(R^(a))R^(b), or C₁₋₆alkylene-S(O)₂N(R^(A))C(O)R^(b), (6) —C₁₋₆ alkyl substituted with HetD,wherein HetD is: (i) a 4- to 7-membered saturated heterocyclic ringcontaining at least one carbon atom and from 1 to 4 heteroatomsindependently selected from N, O and S, wherein the heterocyclic ring isoptionally substituted with from 1 to 5 substituents each of which isindependently halogen, —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl,—O—C₁₋₆ haloalkyl, oxo, —C(═O)N(R^(a))R^(b), —C(═O)C(═O)N(R^(a))R^(b),—C(═O)R^(a), —CO₂R^(a), —S(O)_(n)R^(a), or —SO₂N(R^(a))R^(b); or (ii) a5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatomsindependently selected from N, O and S, wherein the heteroaromatic ringis optionally substituted with from 1 to 4 substituents each of which isindependently —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆haloalkyl, or hydroxy, (7) aryl, which is optionally substituted withfrom 1 to 5 substituents each of which is independently —C₁₋₆alkyl,—C₁₋₆ alkylene-OH, —C₁₋₆alkylene-O—C₁₋₆alkyl, —C₁₋₆ alkylene-O—C₁₋₆haloalkyl, —C₁₋₆ alkylene-N(R^(a))R^(b), —C₁₋₆alkylene-C(═O)N(R^(a))R^(b), —C₁₋₆ alkylene-C(═O)R^(a), —C₁₋₆alkylene-CO₂R^(a), —C₁₋₆ alkylene-S(O)_(n)R^(a), —O—C₁₋₆ alkyl, —C₁₋₆haloalkyl, —O—C₁₋₆ haloalkyl, —OH, halogen, —CN, —NO₂, —N(R^(a))R^(b),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)—C₁₋₆ haloalkyl,—N(R^(a))C(═O)N(R^(a))R^(b), —N(R^(a))CO₂R^(b), —N(R^(a))S(O)_(n)R^(b),—C(═O)N(R^(d))R^(e), —C(═O)R^(a), —CO₂R^(a), —S(O)_(n)R^(a), or—SO₂N(R^(d))R^(e), (8) a 5- or 6-membered heteroaromatic ring containingfrom 1 to 4 heteroatoms independently selected from N, O and S, whereinthe heteroaromatic ring is optionally substituted with from 1 to 4substituents each of which is independently halogen, CN, NO₂, C₁₋₆alkyl, C₁₋₆ haloalkyl, OH, O—C₁₋₆ alkyl, O—C₁₋₆ haloalkyl,N(R^(a))R^(b), C(O)N(R^(a))R^(b), C(O)R^(a), C(O)OR^(a), SR^(a),S(O)R^(a), S(O)₂R^(a), S(O)₂N(R^(a))R^(b), S(O)₂N(R^(a))C(O)R^(b), C₁₋₆alkylene-CN, C₁₋₆ alkylene-NO₂, C₁₋₆ alkylene-OH, C₁₋₆ alkylene-O—C₁₋₆alkyl, C₁₋₆ alkylene-O—C₁₋₆ haloalkyl, C₁₋₆ alkylene-N(R^(a))R^(b), C₁₋₆alkylene-C(O)N(R^(a))R^(b), C₁₋₆ alkylene-C(O)R^(a), C₁₋₆alkylene-C(O)OR^(a), C₁₋₆ alkylene-SR^(a), C₁₋₆ alkylene-S(O)R^(a), C₁₋₆alkylene-S(O)₂R^(a), C₁₋₆ alkylene-S(O)₂N(R^(a))R^(b), or C₁₋₆alkylene-S(O)₂N(R^(a))C(O)R^(b), (9) C₁₋₆ alkyl substituted with —O—C₁₋₆alkyl, —O—C₁₋₆ haloalkyl, —CN, —N(R^(a))R^(b), —C(═O)N(R^(a))R^(b),—C(═O)R^(a), —CO₂R^(a), —S(O)_(n)R^(a), —SO₂N(R^(a))R^(b),—N(R^(a))C(═O)—R^(b), —N(R^(a))CO₂R^(b), or —N(R^(a))SO₂R^(b), or (10)—C₁₋₆ haloalkyl; each aryl is independently (i) phenyl, (ii) a 9- or10-membered bicyclic, fused carbocylic ring system in which at least onering is aromatic, or (iii) an 11- to 14-membered tricyclic, fusedcarbocyclic ring system in which at least one ring is aromatic; eachR^(a) is independently H or C₁₋₆ alkyl; each R^(b) is independently H orC₁₋₆ alkyl; R^(c) is C₁₋₆ haloalkyl or C₁₋₆ alkyl substituted with—C(═O)N(R^(a))R^(b), —C(═O)R^(a), —CO₂R^(a), —S(O)_(n)R^(a),—SO₂N(R^(a))R^(b), N(R^(a))R^(b), —N(R^(a))C(═O)—R^(b),—N(R^(a))CO₂R^(b), or —N(R^(a))SO₂R^(b); each R^(d) and R^(e) areindependently H or C₁₋₆ alkyl, or together with the N atom to which theyare attached form a 4- to 7-membered saturated or mono-unsaturatedheterocyclic ring optionally containing a heteroatom in addition to thenitrogen attached to R^(d) and R^(e) selected from N, O, and S, whereinthe S is optionally oxidized to S(O) or S(O)₂, and wherein the saturatedor mono-unsaturated heterocyclic ring is optionally substituted withfrom 1 to 4 substituents each of which is independently halogen, —CN,—C₁₋₆ alkyl, —OH, oxo, —O—C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —C(═O)R^(a),—CO₂R^(a), —S(O)_(n)R^(a), —SO₂N(R^(a))R^(b), —N(R^(a))C(═O)—R^(b),—N(R^(a))CO₂R^(b), or —N(R^(a))SO₂R^(b); and each n is independently aninteger equal to zero, 1, or 2.